Oxazole derivatives useful as inhibitors of faah

ABSTRACT

The present invention is directed to certain oxazole derivatives which are useful as inhibitors of Fatty Acid Amide Hydrolase (FAAH). The invention is also concerned with pharmaceutical formulations comprising these compounds as active ingredients and the use of the compounds and their formulations in the treatment of certain disorders, including osteoarthritis, rheumatoid arthritis, diabetic neuropathy, postherpetic neuralgia, skeletomuscular pain, and fibromyalgia, as well as acute pain, migraine, sleep disorder, Alzeimer Disease, and Parkinson&#39;s Disease.

BACKGROUND OF THE INVENTION

Disclosed herein are compounds that inhibit the activity of fatty acidamide hydrolase (FAAH), compositions that include the compounds, andmethods of their use. Compounds disclosed herein as inhibitors of fattyacid amide hydrolase (FAAH) are useful in the treatment of diseases,disorders, or conditions that would benefit from the inhibition of fattyacid amide hydrolase and increases in endogenous fatty acid amides.

Fatty acid amide hydrolase (FAAH) is an enzyme that is abundantlyexpressed throughout the CNS (Freund et al. Physiol. Rev. 2003;83:1017-1066) as well as in peripheral tissues, such as, for example, inthe pancreas, brain, kidney, skeletal muscle, placenta, and liver(Giang, D. K. et al., Proc. Natl. Acad. Sci. U.S.A. 1997, 94, 2238-2242;Cravatt et al. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 29,10821-10826). FAAH hydrolyzes the fatty acid amide (FAA) family ofendogenous signaling lipids. General classes of fatty acid amidesinclude the N-acylethanolamides (NAEs) and fatty acid primary amides(FAPAs). Examples of NAEs include anandamide (AEA),palmitoylethanolamide (PEA) and oleoylethanolamide (OEA). An example ofFAPAs includes 9-Z-octadecenamide or oleamide. (McKinney M K. andCravatt B F. 2005. Annu Rev Biochem 74:411-32). Another class of fattyacid amide family of endogenous signaling lipids is N-acyl taurines thathave also been shown to be elevated upon FAAH deletion or inhibition andappear to act on transient receptor potential (TRP) family of calciumchannels, although the functional consequences are not yet clear(Saghatelian A, et al. Biochemistry. 2004, 43:14332-9, Saghatelian A, etal. Biochemistry, 2006, 45:9007-9015). In addition to fatty acid amides,FAAH can also hydrolyze certain fatty acid esters, such as, for example,2-arachidonylglycerol (2-AG) another endocannabinoid (Mechoulam et al.Biochem. Pharmacol. 1995; 50:83-90; Stella et al. Nature, 1997;388:773-778; Suguria et al. Biochem. Biophys. Res. Commun. 1995;215:89-97).

Inhibition of FAAH is expected to lead to an increase in the level ofanandamide and other fatty acid amides. This increase in fatty acidamides leads to an increase in the noiceptive threshold. Thus,inhibitors of FAAH are useful in the treatment of pain (Cravatt, B F;Lichtman, A H Current Opinion in Chemical Biology 2003, 7, 469-475).Such inhibitors are useful in the treatment of other disorders that canbe treated using fatty acid amides or modulators of cannabinoidreceptors, such as, for example, anxiety, sleep disorder, Alzheimerdisease, and Parkinson's disease, eating disorders, metabolic disorders,cardiovascular disorders, and inflammation (Simon et al Archives of Gen.Psychiatry, 2006, 63, 824-830. Kunos, G et al. Pharmacol Rev 2006, 58,389-462). In some embodiments, FAAH inhibitor compounds may beperipherally restricted and may not substantially affect neuraldisorders, such as, for example, depression and anxiety. Finally,agonism of cannabinoid receptors has also been shown to reduce theprogression of atherosclerosis in animal models (see Steffens et al.Nature, 2005, 434, 782-786; and Steffens et al., Curr Opin. Lipid.,2006, 17, 519-526). Thus, increasing the level of endogenouscannabinergic fatty acid amides (e.g., anandamide) is expected toeffectively treat or reduce the risk of developing atherosclerosis.

Inhibition of FAAH also leads to elevation of palmitoylethanolamidewhich is thought to work, in part, through activation of the peroxisomeproliferator-activated receptor α (PPAR-α) to regulate multiple pathwaysincluding, for example, pain perception in neuropathic and inflammatoryconditions such as convulsions, neurotoxicity, spacticity and to reduceinflammation, for example, in atopic eczema and arthritis (LoVerme J etal. The nuclear receptor peroxisome proliferator-activatedreceptor-alpha mediates the anti-inflammatory actions ofpalmitoylethanolamide. Mol Pharmacol 2005, 67, 15-19; LoVerme J et alThe search for the palmitoylethanolamide receptor. Life Sci 2005, 77:1685-1698. Lambert D M et al. The palmitoylethanolamide family: a newclass of anti-inflammatory agents? Curr Med Chem 2002, 9: 663-674;Eberlein B, et al. Adjuvant treatment of atopic eczema: assessment of anemollient containing N-palmitoylethanolamine (ATOPA study). J Eur AcadDermatol Venereol. 2008, 22:73-82. Re G, et al. Palmitoylethanolamide,endocannabinoids and related cannabimimetic compounds in protectionagainst tissue inflammation and pain: potential use in companionanimals. Vet J. 2007 173:21-30.). Thus, inhibition of FAAH is useful forthe treatment of various pain and inflammatory conditions, such asosteoarthritis, rheumatoid arthritis, diabetic neuropathy, postherpeticneuralgia, skeletomuscular pain, and fibromyalgia.

It is also thought that certain fatty acid amides, such as, for example,OEA, act through the peroxisome proliferator-activated receptor α(PPAR-α) to regulate diverse physiological processes, including, e.g.,feeding and lipolysis. Consistent with this, human adipose tissue hasbeen shown to bind and metabolize endocannabinoids such as anandamideand 2-arachidonylglycerol (see Spoto et al., Biochimie 2006, 88,1889-1897; and Matias et al., J. Clin. Endocrin. & Met., 2006, 91,3171-3180). Thus, inhibiting FAAH activity in vivo leads to reduced bodyfat, body weight, caloric intake, and liver triglyceride levels.However, unlike other anti-lipidemic agents that act through. PPAR-α,e.g., fibrates, FAAH inhibitors do not cause adverse side effects suchas rash, fatigue, headache, erectile dysfunction, and, more rarely,anemia, leukopenia, angioedema, and hepatitis (see, e.g., Muscari et al.Cardiology, 2002, 97: 115-121).

Many fatty acid amides are produced on demand and rapidly degraded byFAAH. As a result, hydrolysis by FAAH is considered to be one of theessential steps in the regulation of fatty acid amide levels in thecentral nervous system as well as in peripheral tissues and fluids. Thebroad distribution of FAAH combined with the broad array of biologicaleffects of fatty acid amides (both endocannabinoid andnon-endocannabinoid mechanisms) suggests that inhibition of FAAH leadsto altered levels of fatty acid amides in many tissues and fluids andmay be useful to treat many different conditions. FAAH inhibitorsincrease the levels of endogenous fatty acid amides. FAAH inhibitorsblock the degradation of endocannabinoids and increase the tissue levelsof these endogenous substances. FAAH inhibitors can be used in thisrespect in the prevention and treatment of pathologies in whichendogenous cannabinoids and or any other substrates metabolized by theFAAH enzyme are involved.

The various fatty acid ethanolamides have important and diversephysiological functions. As a result, inhibitor molecules thatselectively inhibit FAAH enzymatic activity would allow a correspondingselective modulation of the cellular and extra-cellular concentrationsof a FAAH substrate. FAAH inhibitors that are biologically compatiblecould be effective pharmaceutical compounds when formulated astherapeutic agents for any clinical indication where FAAH enzymaticinhibition is desired. In some embodiments, FAAH activity in peripheraltissues can be preferentially inhibited. In some embodiments, FAAHinhibitors that do substantially cross the blood-brain-barrier can beused to preferentially inhibit FAAH activity in peripheral tissues. Insome embodiments, FAAH inhibitors that preferentially inhibit FAAHactivity in peripheral tissues can minimize the effects of FAAHinhibition in the central nervous system. In some embodiments, it ispreferred to inhibit FAAH activity in peripheral tissues and minimizeFAAH inhibition in the central nervous system.

SUMMARY OF THE INVENTION

The present invention is directed to certain oxazole derivatives whichare useful as inhibitors of Fatty Acid Amide Hydrolase (FAAH). Theinvention is also concerned with pharmaceutical formulations comprisingthese compounds as active ingredients and the use of the compounds andtheir formulations in the treatment of certain disorders, includingosteoarthritis, rheumatoid arthritis, diabetic neuropathy, postherpeticneuralgia, skeletomuscular pain, and fibromyalgia, as well as acutepain, migraine, sleep disorder, Alzheimer disease, and Parkinson'sdisease.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect the invention is directed to compounds of formula I:

or a pharmaceutically acceptable salt thereof wherein:

X is S or SO;

n is 0, 1 or 2;R¹ is selected from the group consisting of:

(1) aryl, and

(2) HET¹,

wherein R¹ is optionally mono or di-substituted with substituents R⁴ andR⁵; and wherein R⁴ and R⁵ are independently selected from the groupconsisting of:

-   -   (a) halo,    -   (h) —CN,    -   (c) mono, di or tri-halo C₁₋₄ alkyl,    -   (d) mono, di or tri-halo OC₁₋₄ alkyl,    -   (d) —OC₁₋₄ alkyl, optionally substituted with hydroxyl, halo or        amino,    -   (e) —C₁₋₄alkyl optionally substituted with one or two        substituents selected from hydroxyl, CN, —CHF₂ and —CF₃,    -   (f) —C₁₋₂alkyl-C₃₋₆cycloalkyl optionally substituted with        hydroxy, halo or CN,    -   (g) —S(O)_(n)C₁₋₄alkyl,    -   (h) —S(O)_(n)NR⁶R⁷,    -   (i) —C(O)—NH—NR⁸R⁹,    -   (j) —C(O)—OH,    -   (k) —C(O)—OC₁₋₄alkyl, optionally substituted with halo or        hydroxy,    -   (l) —C(O)—NR¹⁰R¹¹,    -   (m) —C(O)—C₁₋₄alkyl optionally mono, di or tri substituted with        halo,    -   (o) —C(NR¹²)—NR¹³R¹⁴,    -   (p) HET⁴,    -   (q) aryl,    -   (r) —C(O)—NH—NH—C(O)H,    -   (s) —CH₂—C(O)—O—C₁₋₄alkyl, whereas the CH₂ may be optionally        substituted with C₁₋₄alkyl or OH    -   (t) —CH₂—C(O)NR¹⁵R¹⁶, whereas the CH₂ may be optionally        substituted with C₁₋₄alkyl or OH, and    -   (u) —NR¹⁷R¹⁸,        wherein choices (p) and (q) are each optionally mono or        di-substituted with substituents selected from    -   (1) halo,    -   (2) —CN,    -   (3) —OH,    -   (4) —C₁₋₄alkyl optionally substituted with hydroxy, halo or        cyano,    -   (5) —CF₃,    -   (6) —OC₁₋₄alkyl optionally substituted with hydroxyl or halo,    -   (7) —C(O)OH, and    -   (8) —C(O)O—C₁₋₃alkyl;    -   (9) —C(O)—NR¹⁹R²⁰,    -   (10) —NH₂,    -   (11) Oxo,    -   (12) ═S,        with the proviso that the substituent on choice (q) is other        than oxo or ═S,        wherein R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷,        R¹⁸, R¹⁹ and R²⁰, are each independently selected from H and        C₁₋₄alkyl,        or        R⁶ and R⁷ or R⁸ and R⁹ or R¹⁰ and R¹¹ or R¹³ and R¹⁴ or R¹⁵ and        R¹⁶ or R¹⁷ and R¹⁸ or R¹⁹ and R²⁰ are joined together to form a        ring with the atoms to which they are attached there is formed a        5-membered heterocyclic ring of 4 to 7 atoms, said ring        containing 1, 2, 3 or 4 heteroatoms selected from N, O and S,        said ring being optionally mono or di-substituted with        substituents independently selected from halo, hydroxyl, oxo,        C₁₋₄alkyl, hydroxyC₁₋₄alkyl, haloC₁₋₄alkyl, —C(O)—C₁₋₄alkyl and        —S(O)nC₁₋₄alkyl;        R² is selected from the group consisting of:

(1) aryl,

(2) HET³,

(3) —CH₂-aryl,

(4) —CH₂—HET³,

(5) —C₁₋₆alkyl, and

(6) —C₃₋₆cycloalkyl,

wherein R² is optionally mono or di-substituted with substituentsindependently selected from the group consisting of

-   -   (a) halo,    -   (b) —CN,    -   (c) —OH,    -   (d) —C₁₋₄alkyl optionally substituted with hydroxy, halo or        cyano,    -   (e) —CF₃,    -   (f) —OC₁₋₄alkyl optionally substituted with hydroxyl or halo,    -   (g) —C(O)O—C₁₋₃alkyl and    -   (h) —S-aryl, optionally substituted with halo, C₁₋₄alkyl or        —OC₁₋₄alkyl;        R³ is selected from the group consisting of:

(1) aryl,

(2) HET⁵, and

(3) C₃₋₆cycloalkyl,

wherein R³ is optionally mono or di-substituted with substituentsindependently selected from the group consisting of

-   -   (a) hydroxy,    -   (b) halo,    -   (c) —C₃₋₆cycloalkyl,    -   (d) —OC₃₋₅cycloalkyl,    -   (e) —C₁₋₄ alkyl,    -   (f) —OC₁₋₄ alkyl,    -   (g) —C(O)CH₃    -   (h) mono, di or tri-halo C₁₋₄ alkyl,    -   (i) mono, di or tri-halo —OC₁₋₄ alkyl, and    -   (j) —S(O)_(n)—C₁₋₄ alkyl;        wherein aryl is as a mono- or bi-cyclic aromatic ring system;        and HET¹, HET², HET³, HET⁴ and HET⁵ are each independently a 5        to 10-membered aromatic, partially aromatic or non-aromatic        mono- or bicyclic ring, or N-oxide thereof, said containing 1 to        4 heteroatoms selected from O, S and N, and optionally        substituted with 1 to 2 oxo groups.

Within this aspect there is a genus wherein:

R¹ is selected from the group consisting of:

(1) phenyl,

(2) pyridyl,

(3) pyridazinyl,

(4) pyrimidyl,

(5) pyrazinyl,

(6) thiazolyl,

(7) thienyl,

(8) pyrrolyl,

(9) oxazolyl, and

(10) oxadiazole;

wherein R¹ is optionally mono or di-substituted with substituents R⁴ andR⁵, wherein R⁴ and R⁵ are independently selected from the groupconsisting of:

-   -   (a) halo,    -   (b) —CN,    -   (c) mono, di or tri-halo C₁₋₄ alkyl,    -   (d) —O—C₁₋₄alkyl, optionally substituted with hydroxyl, halo or        amino    -   (e) —C₁₋₄alkyl optionally substituted with hydroxyl or CN,    -   (f) —C₁₋₂alkyl-C₃₋₆cycloalkyl optionally substituted with        hydroxy,    -   (h) —S(O)_(n)C₁₋₄alkyl wherein n is 0, 1 or 2,    -   (i) —S(O)_(n)NR⁶R⁷,    -   (j) —C(O)—NR¹⁰R¹¹,    -   (k) HET⁴,    -   (l) aryl, and        wherein choices (k) and (l) are each optionally mono or        di-substituted with substituents selected from    -   (1) halo,    -   (2) —CN,    -   (3) —OH,    -   (4) —C₁₋₄alkyl optionally substituted with hydroxy, halo or        cyano,    -   (5) —CF₃,    -   (6) —OC₁₋₄alkyl optionally substituted with hydroxyl or halo,    -   (7) —C(O)OH,    -   (8) —C(O)O—C₁₋₃alkyl, and    -   (9) —C(O)—NR¹⁹R²⁰,        wherein R⁶, R⁷, R¹⁰, R¹¹, R¹⁹ and R²⁰ are each independently        selected from H and C₁₋₄alkyl.

Within this genus there is a sub-genus wherein:

R¹ is selected from the group consisting of:

(1) phenyl,

(2) pyridyl,

(3) pyrimidyl,

(4) pyrazinyl,

(5) pyridazinyl,

(6) 1,2,4-oxadiazolyl, and

(7) 1,3,4-oxadiazolyl,

optionally mono or di-substituted with substituents R⁴ and R⁵, which areindependently selected from the group consisting of

-   -   (a) —C₁₋₄alkyl optionally substituted with hydroxy,    -   (b) —S(O)_(n)C₁₋₄alkyl,    -   (c) —C(O)—NR¹⁰R¹¹,    -   (d) HET⁴, and    -   (e) halo,        wherein HET⁴ is optionally mono or di-substituted with        substituents selected from:    -   (1) halo,    -   (2) —CN,    -   (3) —OH,    -   (4) —C₁₋₄alkyl optionally substituted with hydroxy, halo or        cyano,    -   (5) —CF₃,    -   (6) —OC₁₋₄alkyl optionally substituted with hydroxyl or halo,    -   (7) —C(O)OH, and    -   (8) —C(O)O—C₁₋₃alkyl, and    -   (9) —C(O)—NR¹⁹R²⁰,        wherein R¹⁰, R¹¹, R¹⁹ and R²⁰ are each independently selected        from H and C₁₋₄alkyl.

Within this aspect there is a genus wherein:

R² is selected from the group consisting of:

(1) aryl,

(2) HET³,

(3) —CH₂aryl, and

(4) —CH₂HET³,

wherein R² is optionally mono or di-substituted with substituentsindependently selected from the group consisting of:

-   -   (a) halo,    -   (b) —CN,    -   (c) —OH,    -   (d) —Hydroxy C₁₋₄alkyl,    -   (e) —C₁₋₄alkyl,    -   (f) —C₁₋₄haloalkyl, and    -   (g) —OC₁₋₄alkyl, optionally substituted with halo or hydroxyl.

Within this genus there is a sub-genus wherein:

R² is selected from the group consisting of:

(1) aryl, and

(2) HET³,

wherein R² is optionally mono or di-substituted with substituentsindependently selected from the group consisting of

-   -   (a) halo,    -   (b) —CN,    -   (c) —OH,    -   (d) -hydroxy C₁₋₄alkyl,    -   (e) —CH₃,    -   (f) —CF₃, and    -   (g) —OCH₃.

Within this sub-genus there is a class wherein:

R² is selected from the group consisting of:

(1) phenyl,

(2) pyridyl,

(3) pyridazinyl,

(4) pyrimidyl,

(5) pyrazinyl,

(6) thiazolyl,

(7) oxazolyl,

(8) pyrazolyl,

(9) 1,2,4-oxadiazolyl, and

(10) 1,3,4-oxadiazolyl,

wherein R² is optionally mono or di-substituted with halo, OC₁₋₄alkyloptimally sunstituted with halogen, —C₁₋₄haloalkyl, hydroxyl and CN.

Within this aspect there is a genus wherein:

R³ is selected from the group consisting of:

(1) aryl, and

(2) HET⁵,

wherein choice (1) and (2) are each optionally mono or di-substitutedwith substituents independently selected from the group consisting of:

-   -   (a) halo,    -   (b) —C₃₋₆cycloalkyl,    -   (c) —OC₁₋₄ alkyl,    -   (d) mono, di or tri-halo C₁₋₄ alkyl, and    -   (e) mono, di or tri-halo —OC₁₋₄ alkyl.

Within this genus there is a sub-genus wherein:

R³ is selected from the group consisting of:

(1) phenyl,

(2) pyrimidyl,

(3) pyridyl,

-   -   wherein R³ is optionally mono or di-substituted with halo,        haloC₁₋₄alkyl, or —OC₁₋₄alkyl optionally substituted with halo.

Within this aspect there is a genus wherein X is S.

Within this aspect there is a genus of the Formula

whereinR¹ is selected from the group consisting of:

(1) phenyl,

(2) pyridyl,

(3) pyridazinyl,

(4) pyrimidyl,

(5) pyrazinyl,

(6) thiazolyl,

(7) thienyl,

(8) pyrrolyl,

(9) oxazolyl, and

(10) oxadiazole;

wherein R¹ is optionally mono or di-substituted with substituents R⁴ andR⁵, which are independently selected from the group consisting of

-   -   (a) halo,    -   (b) —CN,    -   (c) mono, di or tri-halo C₁₋₄ alkyl,    -   (d) —O—C₁₋₄alkyl, optionally substituted with hydroxyl, halo or        amino    -   (e) —C₁₋₄alkyl optionally substituted with hydroxyl or CN,    -   (f) —C₁₋₂alkyl-C₃₋₆cycloalkyl optionally substituted with        hydroxy,    -   (h) —S(O)_(n)C₁₋₄alkyl wherein n is 0, 1 or 2,    -   (i) —S(O)_(n)NR⁶R⁷,    -   (j) —C(O)—NR¹⁰R¹¹,    -   (k) HET⁴,    -   (l) aryl, and        wherein choices (k) and (l) are each optionally mono or        di-substituted with substituents selected from    -   (1) halo,    -   (2) —CN,    -   (3) —OH,    -   (4) —C₁₋₄alkyl optionally substituted with hydroxy, halo or        cyano,    -   (5) —CF₃,    -   (6) —OC₂₋₄alkyl optionally substituted with hydroxyl or halo,    -   (7) —C(O)OH,    -   (8) —C(O)O—C₁₋₃alkyl, and    -   (9) —C(O)—NR¹⁹R²⁰,        wherein R⁶, R⁷, R¹⁰, R¹¹, R¹⁹ and R²⁰, are each independently        selected from H and C₁₋₄alkyl; R² is selected from the group        consisting of:

(1) aryl,

(2) HET³,

(3) —C₁₋₆alkyl, and

(4) —C₃₋₆cycloalkyl,

wherein choice R² is optionally mono or di-substituted with substituentsindependently selected from the group consisting of

-   -   (a) halo,    -   (b) —CN,    -   (c) —OH,    -   (d) -hydroxy C₁₋₄alkyl,    -   (e) —C₁₋₄alkyl,    -   (f) —C₁₋₄haloalkyl, and    -   (g) —OC₁₋₄alkyl, optionally substituted with halo or hydroxyl;        and        R³ is selected from the group consisting of:

(1) aryl, and

(2) HET⁵,

wherein choice (1) and (2) are each optionally mono or di-substitutedwith substituents independently selected from the group consisting of

-   -   (a) halo,    -   (b) —C₃₋₆cycloalkyl,    -   (c) —C₁₋₄ alkyl,    -   (d) —OC₁₋₄ alkyl,    -   (e) mono, di or tri-halo C₁₋₄ alkyl, and    -   (f) mono, di or tri-halo —OC₁₋₄ alkyl.

Within this genus there is a sub-genus wherein:

R¹ is selected from the group consisting of:

(1) phenyl,

(2) pyridinyl,

(3) pyrimidinyl,

(4) pyrazinyl,

(5) pyridazinyl,

(6) 1,2,4-oxadiazolyl, and

(7) 1,3,4-oxadiazolyl,

optionally mono or di-substituted with substituents R⁴ and R⁵, which areindependently selected from the group consisting of

-   -   (a) —C₁₋₄alkyl optionally substituted with hydroxy,    -   (b) —S(O)_(n)C₁₋₄alkyl,    -   (c) —C(O)—NR¹⁰R¹¹,    -   (d) HET⁴, and    -   (e) halo,        wherein HET⁴ is optionally mono or di-substituted with        substituents selected from:    -   (1) halo,    -   (2) —CN,    -   (3) —OH,    -   (4) —C₁₋₄alkyl optionally substituted with hydroxy, halo or        cyano,    -   (5) —CF₃,    -   (6) —OC₁₋₄alkyl optionally substituted with hydroxyl or halo,    -   (7) —C(O)OH, and    -   (8) —C(O)O—C₁₋₃alkyl, and    -   (9) —C(O)—NR¹⁹R²⁰,        wherein R¹⁰, R¹¹, R¹⁹ and R²⁰ are each independently selected        from H and C₁₋₄alkyl. R² is selected from the group consisting        of:

(1) phenyl,

(2) pyridyl,

(3) pyridazinyl,

(4) pyrimidyl,

(5) pyrazinyl,

(6) thiazolyl,

(7) oxazolyl,

(8) pyrazolyl,

(9) 1,2,4-oxadiazolyl, and

(10) 1,3,4-oxadiazolyl,

wherein R² is optionally mono or di-substituted with halo, OC₁₋₄alkyloptially sunstituted with halogen, —C₁₋₄haloalkyl, hydroxyl and CN; andR³ is selected from the group consisting of:

(1) phenyl,

(2) pyrimidyl,

(3) pyridyl,

-   -   wherein R³ is optionally mono or di-substituted with halo,        haloC₁₋₄alkyl, or —OC₁₋₄alkyl optionally substituted with halo.

Within this genus there is a sub-genus of the Formula

wherein:R¹ is selected from the group consisting of:

(1) phenyl,

(2) pyridyl,

(3) pyridazinyl,

(4) pyrimidyl,

(5) pyrazinyl,

wherein R¹ is optionally mono or di-substituted with substituents R⁴ andR⁵, which are independently selected from the group consisting of

-   -   (a) halo,    -   (b) —CN,    -   (c) mono, di or tri-halo C₁₋₄ alkyl,    -   (d) —O—C₁₋₄alkyl, optionally substituted with hydroxyl, halo or        amino    -   (e) —C(CH₃)₂—OH;        R² is selected from the group consisting of:

(1) phenyl,

(2) pyridyl,

(3) pyridazinyl,

(4) pyrimidyl,

(5) pyrazinyl,

(6) pyrazolyl,

wherein R² is optionally mono or di-substituted with halo, OC₁₋₄alkyloptially sunstituted with halogen, —C₁₋₄haloalkyl, hydroxyl and CN; andR³ is selected from the group consisting of:

(1) phenyl,

(2) pyrimidyl,

(3) pyridyl,

-   -   wherein R³ is optionally mono or di-substituted with halo,        haloC₁₋₄alkyl, or —OC₁₋₄alkyl optionally substituted with halo.

Within this sub-genus there is a class wherein:

-   -   13. A compound of Claim 12 wherein:        R¹ is selected from the group consisting of:

(1) phenyl,

(2) pyridyl,

(3) pyrazinyl,

wherein R¹ is optionally mono or di-substituted with substituents R⁴ andR⁵, which are independently selected from the group consisting of:

-   -   (a) halo,    -   (b) —CN,    -   (c) mono, di or tri-halo C₁₋₄ alkyl,    -   (d) —O—C₁₋₄alkyl, optionally substituted with hydroxyl, halo or        amino    -   (e) —C(CH₃)₂—OH;        R² is selected from the group consisting of:    -   (1) phenyl,    -   (2) pyridyl,        wherein R² is optionally mono or di-substituted with halo,        OC₁₋₄alkyl optially sunstituted with halogen, —C₁₋₄haloalkyl,        hydroxyl and CN; and        R³ is selected from the group consisting of:

(1) phenyl,

(2) pyrimidyl,

(3) pyridyl,

-   -   wherein R³ is optionally mono or di-substituted with halo,        haloC₁₋₄alkyl, or —OC₁₋₄alkyl optionally substituted with halo.

The compounds of the present invention may contain one or moreasymmetric centers and can thus occur as racemates and racemic mixtures,single enantiomers, diastereomeric mixtures and individualdiastereomers. Additional asymmetric centers may be present dependingupon the nature of the various substituents on the molecule. Each suchasymmetric center will independently produce two optical isomers and itis intended that all of the possible optical isomers and diastereomersin mixtures and as pure or partially purified compounds are includedwithin the ambit of this invention. The present invention is meant tocomprehend all such isomeric forms of these compounds. Formula I showsthe structure of the class of compounds without preferredstereochemistry. The independent syntheses of these diastereomers ortheir chromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochcmistry may be determined by the x-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration. If desired, racemic mixtures ofthe compounds may be separated so that the individual enantiomers areisolated. The separation can be carried out by methods well known in theart, such as the coupling of a racemic mixture of compounds to anenantiomerically pure compound to form a diastereomeric mixture,followed by separation of the individual diastereomers by standardmethods, such as fractional crystallization or chromatography. Thecoupling reaction is often the formation of salts using anenantiomerically pure acid or base. The diasteromeric derivatives maythen be converted to the pure enantiomers by cleavage of the addedchiral residue. The racemic mixture of the compounds can also beseparated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.Alternatively, any enantiomer of a compound may be obtained bystereoselective synthesis using optically pure starting materials orreagents of known configuration by methods well known in the art.

The invention is described using the following definitions unlessotherwise indicated.

The term “halogen” or “halo” includes F, Cl, Br, and I.

The term “alkyl” means linear or branched structures and combinationsthereof, having the indicated number of carbon atoms. Thus, for example,C₁₋₆alkyl includes methyl, ethyl, propyl, 2-propyl, s- and t-butyl,butyl, pentyl, hexyl, 1,1-dimethylethyl.

The term “alkoxy” means alkoxy groups of a straight, branched or cyclicconfiguration having the indicated number of carbon atoms. C₁₋₆alkoxy,for example, includes methoxy, ethoxy, propoxy, isopropoxy, and thelike.

The term “alkylthio” means alkylthio groups having the indicated numberof carbon atoms of a straight, branched or cyclic configuration.C₁₋₆alkylthio, for example, includes methylthio, propylthio,isopropylthio, and the like.

The term “alkenyl” means linear or branched structures and combinationsthereof, of the indicated number of carbon atoms, having at least onecarbon-to-carbon double bond, wherein hydrogen may be replaced by anadditional carbon-to-carbon double bond. C₂₋₆alkenyl, for example,includes ethenyl, propenyl, 1-methylethenyl, butenyl and the like.

The term “alkynyl” means linear or branched structures and combinationsthereof, of the indicated number of carbon atoms, having at least onecarbon-to-carbon triple bond. C₃₋₆alkynyl, for example, includespropynyl, 1-methylethynyl, butynyl and the like.

The term “cycloalkyl” means mono-, bi- or tri-cyclic structures,optionally combined with linear or branched structures, the indicatednumber of carbon atoms. Examples of cycloalkyl groups includecyclopropyl, cyclopentyl, cycloheptyl, adamantyl, cyclododecylmethyl,2-ethyl-1-bicyclo[4.4.0]decyl, and the like.

The term “aryl” is defined as a mono- or bi-cyclic aromatic ring systemand includes, for example, phenyl, naphthyl, and the like.

The term “aralkyl” means an alkyl group as defined above of 1 to 6carbon atoms with an aryl group as defined above substituted for one ofthe alkyl hydrogen atoms, for example, benzyl and the like.

The term “aryloxy” means an aryl group as defined above attached to amolecule by an oxygen atom (aryl-O) and includes, for example, phenoxy,naphthoxy and the like.

The term “aralkoxy” means an aralkyl group as defined above attached toa molecule by an oxygen atom (aralkyl-O) and includes, for example,benzyloxy, and the like.

The term “arylthio” is defined as an aryl group as defined aboveattached to a molecule by a sulfur atom (aryl-S) and includes, forexample, thiophenyoxy, thionaphthoxy and the like.

The term “aroyl” means an aryl group as defined above attached to amolecule by an carbonyl group (aryl-C(O)—) and includes, for example,benzoyl, naphthoyl and the like.

The term “aroyloxy” means an aroyl group as defined above attached to amolecule by an oxygen atom (aroyl-O) and includes, for example,benzoyloxy or benzoxy, naphthoyloxy and the like.

The term “HET”, such as in “HET¹”, “HET²”, “HET³”, “HET⁴”, and “HET⁵” isdefined as a 5- to 10-membered aromatic, partially aromatic ornon-aromatic mono- or bicyclic ring, containing 1-4 heteroatoms selectedfrom O, S and N, and optionally substituted with 1-2 oxo groups. Whereapplicable, the Het group shall be defined to include the N-oxide.Preferably, “HET” is a 5- or 6-membered aromatic or non-aromaticmonocyclic ring containing 1-3 heteroatoms selected from O, S and N, forexample, pyridine, pyrimidine, pyridazine, furan, thiophene, thiazole,oxazole, isooxazole and the like, or HET is a 9- or 10-membered aromaticor partially aromatic bicyclic ring containing 1-3 heteroatoms selectedfrom O, S, and N, for example, benzofuran, benzothiophene, indole,pyranopyrrole, benzopyran, quionoline, benzocyclohexyl, naphtyridine andthe like. “HET” also includes the following: benzimidazolyl,benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl,benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl,indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl,isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl,oxazolyl, pyrazinyl, pyrazolyl, pyridopyridinyl, pyridazinyl, pyridyl,pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, thiadiazolyl,thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl,hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl,thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl,dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl,dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl,dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl,dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl. In oneaspect “HET” is selected from pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, thienyl, pyrrolyl, oxazolyl, and oxadiazole;

For all of the above definitions, each reference to a group isindependent of all other references to the same group when referred toin the Specification. For example, if both R¹ and R² are HET, thedefinitions of HET are independent of each other and R¹ and R² may bedifferent HET groups, for example furan and thiophene.

The ability of the compounds of Formula I to selectively inhibit FAAHmakes them useful for treating, preventing or reversing the progressionof a variety of inflammatory and non-inflammatory diseases andconditions.

Diseases, disorders, syndromes and/or conditions, that would benefitfrom inhibition of FAAH enzymatic activity include, for example,Alzheimer's Disease, schizophrenia, depression, alcoholism, addiction,suicide, Parkinson's disease, Huntington's disease, stroke, emesis,miscarriage, embryo implantation, endotoxic shock, liver cirrhosis,atherosclerosis, cancer, traumatic head injury, glaucoma, and bonecement implantation syndrome.

Other diseases, disorders, syndromes and/or conditions that wouldbenefit from inhibition of FAAH activity, include, for example, multiplesclerosis, retinitis, amyotrophic lateral sclerosis, immunodeficiencyvirus-induced encephalitis, attention-deficit hyperactivity disorder,pain, nociceptive pain, neuropathic pain, inflammatory pain,noninflammatory pain, painful hemorrhagic cystitis, obesity,hyperlipidemia, metabolic disorders, feeding and fasting, alteration ofappetite, stress, memory, aging, hypertension, septic shock, cardiogenicshock, intestinal inflammation and motility, irritable bowel syndrome,colitis, diarrhea, ileitis, ischemia, cerebral ischemia, hepaticischemia, myocardial infarction, cerebral excitotoxicity, seizures,febrile seizures, neurotoxicity, neuropathies, sleep, induction ofsleep, prolongation of sleep, insomnia, and inflammatory diseases.Neurological and psychological disorders that would benefit frominhibition of FAAH activity include, for example, pain, depression,anxiety, generalized anxiety disorder (GAD), obsessive compulsivedisorders, stress, stress urinary incontinence, attention deficithyperactivity disorders, schizophrenia, psychosis, Parkinson's disease,muscle spasticity, epilepsy, diskenesia, seizure disorders, jet lag, andinsomnia.

FAAH inhibitors can also be used in the treatment of a variety ofmetabolic syndromes, diseases, disorders and/or conditions, includingbut not limited to, insulin resistance syndrome, diabetes,hyperlipidemia, fatty liver disease, obesity, atherosclerosis andarteriosclerosis. FAAH inhibitors are useful in the treatment of avariety of painful syndromes, diseases, disorders and/or conditions,including but not limited to those characterized by non-inflammatorypain, inflammatory pain, peripheral neuropathic pain, central pain,deafferentiation pain, chronic nociceptive pain, stimulus of nociceptivereceptors, phantom and transient acute pain.

Inhibition of FAAH activity can also be used in the treatment of avariety of conditions involving inflammation. These conditions include,but are not limited to arthritis (such as rheumatoid arthritis, shouldertendonitis or bursitis, gouty arthritis, and aolymyalgia rheumatica),organ-specific inflammatory diseases (such as thyroiditis, hepatitis,inflammatory bowel diseases), asthma, other autoimmune diseases (such asmultiple sclerosis), chronic obstructive pulmonary disease (COPD),allergic rhinitis, and cardiovascular diseases.

In some cases, FAAH inhibitors are useful in preventingneurodegeneration or for neuroprotection.

In addition, it has been shown that when FAAH activity is reduced orabsent, one of its substrates, anandamide, acts as a substrate forCOX-2, which converts anandamide to prostamides (Weber et al J Lipid.Res. 2004; 45:757). Concentrations of certain prostamides may beelevated in the presence of a FAAH inhibitor. Certain prostamides areassociated with reduced intraocular pressure and ocular hypotensivity.Thus, in one embodiment, FAAH inhibitors may be useful for treatingglaucoma.

In some embodiments, FAAH inhibitors can be used to treat or reduce therisk of EMDs, which include, but are not limited to, obesity, appetitedisorders, overweight, cellulite, Type I and Type I1 diabetes,hyperglycemia, dyslipidemia, steatohepatitis, liver steatosis,non-alcoholic steatohepatitis, Syndrome X, insulin resistance, diabeticdyslipidemia, anorexia, bulimia, anorexia nervosa, hyperlipidemia,hypertriglyceridemia, atherosclerosis, arteriosclerosis, inflammatorydisorders or conditions, Alzheimer's disease, Crohn's disease, vascularinflammation, inflammatory bowel disorders, rheumatoid arthritis,asthma, thrombosis, or cachexia.

In other embodiments, FAAH inhibitors can be used to treat or reduce therisk of insulin resistance syndrome and diabetes, i.e., both primaryessential diabetes such as Type I Diabetes or Type I1 Diabetes andsecondary nonessential diabetes. Administering a composition containinga therapeutically effective amount of an in vivo FAAH inhibitor reducesthe severity of a symptom of diabetes or the risk of developing asymptom of diabetes, such as atherosclerosis, hypertension,hyperlipidemia, liver steatosis, nephropathy, neuropathy, retinopathy,foot ulceration, or cataracts.

In another embodiment, FAAH inhibitors can be used to treat food abusebehaviors, especially those liable to cause excess weight, e.g.,bulimia, appetite for sugars or fats, and non-insulin-dependentdiabetes.

In some embodiments, FAAH inhibitors can be used to treat a subjectsuffering from an EMD and also suffers from a depressive disorder orfrom an anxiety disorder. Preferably, the subject is diagnosed assuffering from the depressive or psychiatric disorder prior toadministration of the FAAH inhibitor composition. Thus, a dose of a FAAHinhibitor that is therapeutically effective for both the EMD and thedepressive or anxiety disorder is administered to the subject.

Preferably, the subject to be treated is human. However, the methods canalso be used to treat non-human mammals. Animal models of EMDs such asthose described in, e.g., U.S. Pat. No. 6,946,491 are particularlyuseful.

FAAH inhibitor compositions can also be used to decrease body-weight inindividuals wishing to decrease their body weight for cosmetic, but notnecessarily medical considerations.

A FAAH inhibitor composition can be administered in combination with adrug for lowering circulating cholesterol levels (e.g., statins, niacin,fibric acid derivatives, or bile acid binding resins). FAAH inhibitorcompositions can also be used in combination with a weight loss drug,e.g., orlistat or an appetite suppressant such as diethylpropion,mazindole, orlistat, phendimetrazine, phentermine, or sibutramine.

The term “treating” encompasses not only treating a patient to relievethe patient of the signs and symptoms of the disease or condition butalso prophylactically treating an asymptomatic patient to prevent theonset of the disease or condition or preventing, slowing or reversingthe progression of the disease or condition. The term “amount effectivefor treating” is intended to mean that amount of a drug orpharmaceutical agent that will elicit the biological or medical responseof a tissue, a system, animal or human that is being sought by aresearcher, veterinarian, medical doctor or other clinician. The termalso encompasses the amount of a pharmaceutical drug that will preventor reduce the risk of occurrence of the biological or medical event thatis sought to be prevented in a tissue, a system, animal or human by aresearcher, veterinarian, medical doctor or other clinician.

The term “treating” encompasses not only treating a patient to relievethe patient of the signs and symptoms of the disease or condition butalso prophylactically treating an asymptomatic patient to prevent theonset of the discase or condition or preventing, slowing or reversingthe progression of the disease or condition. The term “amount effectivefor treating” is intended to mean that amount of a drug orpharmaceutical agent that will elicit the biological or medical responseof a tissue, a system, animal or human that is being sought by aresearcher, veterinarian, medical doctor or other clinician. The termalso encompasses the amount of a pharmaceutical drug that will preventor reduce the risk of occurrence of the biological or medical event thatis sought to be prevented in a tissue, a system, animal or human by aresearcher, veterinarian, medical doctor or other clinician.

The following abbreviations have the indicated meanings:

-   -   AIBN=2.2′-azobisisobutyronitrile    -   B.P.=benzoyl peroxide    -   Bn=benzyl    -   CCl₄=carbon tetrachloride    -   D=—O(CH₂)₃O    -   DAST=diethylamine sulfur trifluoride    -   DCC=dicyclohexyl carbodiimide    -   DCI=1-(3-dimethylaminopropyl)-3-ethyl carbodiimide    -   DEAD=diethyl azodicarboxylate    -   DIBAL=diisobutyl aluminum hydride    -   DME=ethylene glycol dimethylether    -   DMAP=4-(dimethylamino)pyridine    -   DMF=N,N-dimethylformamide    -   DMSO=dimethyl sulfoxide    -   Et₃N=triethylamine    -   LDA=lithium diisopropylamide    -   m-CPBA=metachloroperbenzoic acid    -   NBS=N-bromosuccinimide    -   NSAID=non-steroidal anti-inflammatory drug    -   PCC=pyridinium chlorochromate    -   PDC=pyridinium dichromate    -   Ph=phenyl    -   1,2-Ph=1,2-benzenediyl    -   Pyr=pyridinediyl    -   Qn=7-chloroquinolin-2-yl    -   R^(S)=—CH₂SCH₂CH₂Ph    -   r.t.=room temperature    -   rac.=racemic    -   THF=tetrahydrofuran    -   THP=tetrahydropyran-2-yl

Alkyl Group Abbreviations

-   -   Me=methyl    -   Et=ethyl    -   n-Pr=normal propyl    -   i-Pr=isopropyl    -   n-Bu=normal butyl    -   i-Bu=isobutyl    -   s-Bu=secondary butyl    -   t-Bu=tertiary butyl    -   c-Pr=cyclopropyl    -   c-Bu=cyclobutyl    -   c-Pen=cyclopentyl    -   c-Hex=cyclohexyl

Some of the compounds described herein contain one or more asymmetriccenters and may thus give rise to diastereomers and optical isomers. Thepresent invention is meant to comprehend such possible diastereomers aswell as their racemic and resolved, enantiomerically pure forms andpharmaceutically acceptable salts thereof.

Some of the compounds described herein contain olefinic double bonds,and unless specified otherwise, are meant to include both E and Zgeometric isomers.

The pharmaceutical compositions of the present invention comprise acompound of Formula I as an active ingredient or a pharmaceuticallyacceptable salt, thereof, and may also contain a pharmaceuticallyacceptable carrier and optionally other therapeutic ingredients. Theterm “pharmaceutically acceptable salts” refers to salts prepared frompharmaceutically acceptable non-toxic bases including inorganic basesand organic bases. Salts derived from inorganic bases include aluminum,ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganicsalts, manganous, potassium, sodium, zinc, and the like. Particularlypreferred are the ammonium, calcium, magnesium, potassium, and sodiumsalts. Salts derived from pharmaceutically acceptable organic non-toxicbases include salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines, and basic ion exchange resins, such as arginine, betaine,caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic,glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, andthe like. Particularly preferred are citric, hydrobromic, hydrochloric,maleic, phosphoric, sulfuric, and tartaric acids.

It will be understood that in the discussion of methods of treatmentwhich follows, references to the compounds of Formula I are meant toalso include the pharmaceutically acceptable salts.

The magnitude of prophylactic or therapeutic dose of a compound ofFormula I will, of course, vary with the nature and the severity of thecondition to be treated and with the particular compound of Formula Iand its route of administration. It will also vary according to avariety of factors including the age, weight, general health, sex, diet,time of administration, rate of excretion, drug combination and responseof the individual patient. In general, the daily dose from about 0.001mg to about 100 mg per kg body weight of a mammal, preferably 0.01 mg toabout 10 mg per kg. On the other hand, it may be necessary to usedosages outside these limits in some cases.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, aformulation intended for oral administration to humans may contain fromabout 0.5 mg to about 5 g of active agent compounded with an appropriateand convenient amount of carrier material which may vary from about 5 toabout 95 percent of the total composition. Dosage unit forms willgenerally contain from about 1 mg to about 2 g of an active ingredient,typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg,800 mg, or 1000 mg.

For the treatment of FAAH mediated diseases the compound of Formula Imay be administered orally, topically, parenterally, by inhalation sprayor rectally in dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.The term parenteral as used herein includes subcutaneous, intravenous,intramuscular, intrasternal injection or infusion techniques. Inaddition to the treatment of warm-blooded animals such as mice, rats,horses, cattle, sheep, dogs, cats, etc., the compound of the inventionis effective in the treatment of humans.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, solutions, aqueous or oily suspensions, dispersible powders orgranules, emulsions, hard or soft capsules, syrups or elixirs.Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavouringagents, colouring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example, magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. They may also becoated by the technique described in the U.S. Pat. Nos. 4,256,108;4,166,452; and 4,265,874 to form osmotic therapeutic tablets for controlrelease.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredients is mixed withwater-miscible solvents such as propylene glycol, PEGS and ethanol, oran oil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more colouringagents, one or more flavouring agents, and one or more sweeteningagents, such as sucrose, saccharin or aspartame.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavouring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavouring and colouringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof an oil-in-water emulsion. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavouring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavouring and colouringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. Cosolvents suchas ethanol, propylene glycol or polyethylene glycols may also be used.In addition, sterile, fixed oils are conventionally employed as asolvent or suspending medium. For this purpose any bland fixed oil maybe employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

The compounds of Formula I may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ambient temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are cocoa butter and polyethylene glycols.

For topical use, creams, ointments, gels, solutions or suspensions,etc., containing a compound of Formula I are employed. (For purposes ofthis application, topical application shall include mouth washes andgargles.) Topical formulations may generally be comprised of apharmaceutical carrier, cosolvent, emulsifier, penetration enhancer,preservative system, and emollient.

Assays

The following assays illustrate the utility of the invention:

The compounds of the invention underwent pharmacological evaluations todetermine their inhibitory effect on the enzyme FAAH (Fatty Acid AmideHydrolase).

To assist in assay development stable cell lines for human, murine andrat full length FAAH were developed. Human FAAH cDNA (Acccssion No:NM_(—)001441.1) was purchased from Origene (Rockville, Md.). The fulllength FAAH was subcloned into the mammalian expression vector,pcDEF.neo, using XbaI and EcoRI restriction sites and used for stablecell line generation.

Con- struct Primer Sequence Full   1 CAAGGTACCGCCAC lengthCATGGTGCTGAGCG rodent AAGTGTGG FAAH Full   2 CCGGAATTCTCAAGA lengthTGGCCGCTTTTCAGG murine FAAH Full   3 CCGGAATTCTCACGA lengthTGGCTGCTTTTGAGG rat FAAH

Murine (accession number NM_(—)010173) and Rat FAAH (accession numberNM_(—)024132) was amplified by reverse transcriptase polymerase chainreaction (RT-PCR) from brain cDNA (BD Biosciences, San Jose, Calif.)using primers 1 and 2 or primers 1 and 3 respectively (see Table). Theresulting PCR product was ligated into pCR4 TOPO and DNA sequenceconfirmed. The full length murine FAAH was subcloned into the mammalianexpression vector, pcDEFneo using either EcoRI (murine) or KpnI andEcoRI (rat) restriction sites. Chinese hamster ovary cells (CHO) weretransfected following manufacturers protocol (AMAXA). Forty eight hourspost transfection, cells were trypsinized and transferred to 96 wellplates in Iscove's DMEM media supplemented with 2 mM Glutamine, 10%fetal calf serum, 1 mg/ml geneticin and HT Supplement (0.1 mM sodiumhypoxanthine, 0.016 mM thymidine) in order to isolate single clones.Following selection in geneticin, individual clones were selected andFAAH activity was assessed using a whole cell fluorescent anandamideassay, modified from Ramarao et al (2005). Following removal of tissueculture media cells were dislodged following addition of Cellstripper(Mediatech, Inc. Manassas, Va.) and transferred to 96 well black clearbottom assay plate, centrifuged at 1,000 rpm for 3 mins and mediaremoved and replaced with assay buffer (50 mM Tris pH8.0, 1 mM EDTA,0.1% fatty acid free BSA). The reaction was initiated by addition offluorescent substrate, AMC Arachidonoyl Amide (Cayman Chemical, AnnArbor, Mich.) to 1 μM and reaction allowed to proceed for 2 hours atroom temperature. Release of fluorescence was monitored in a CytoFluorMultiplate Reader. Cells expressing the highest amount of FAAH activitywere selected for study with FAAH inhibitors.

Preparation of Lysate and Microsomes

CHO cells expressing FAAH were used to prepare either crude cell lysateor microsome fractions. To harvest cells, tissue culture media wasdecanted, the monolayer washed three times with Ca⁺⁺Mg⁺⁺ free PBS andcells recovered after 15 min in enzyme free dissociation media(Millipore Corp, Billerica, Mass.). Cells were collected by centrifugingat 2000 rpm for 15 min. and the cell pellet re-suspended with 50 mMHEPES (pH 7.4) containing 1 mM EDTA and the protease inhibitorsaprotinin (1 mg/ml) and leupeptin (100 μM). The suspension was sonicatedat 4° C. and the cell lysate recovered after centrifuging at 12,000×g(14,600 rpm, SS34 rotor) for 20 min at 4° C. to form a crude pellet ofcell debris, nuclei, peroxisomes, lysosomes, and mitochondria; thesupernatant or cell lysate was used for FAAH enzyme assay. In somecases, microsomes fractions enriched in FAAH were prepared bycentrifuging the cell lysate further at 27,000 rpm (100,000×g) in SW28rotor for 50 minutes at 4° C. The pellet containing FAAH-enrichedmicrosomes was re-suspend in 50 mM HEPES, (pH 7.4) 1 mM EDTA, and anyremaining DNA sheared by passage of material through a 23 gauge needleand aliquots of enzyme were store at −80° C. prior to use.

FAAH Assays

Several assays have been used to demonstrate the inhibitory activity.Enzyme activity was demonstrated in a radioenzymatic test based onmeasuring the product of hydrolysis (ethanolamine [³H]) of anandamide[ethanolamine 1-.sup.3H](American Radiolabeled Chemicals; 1 mCi/ml) withFAAH (Life Sciences (1995), 56, 1999-2005 and Journal of Pharmacologyand Experimented Therapeutics (1997), 283, 729-734), Analytical.Biochemistry (2003), 318, 270-5. In addition, routine assays wereperformed monitoring hydrolysis of arachidonyl-7-amino-4-methylcoumarinamide (AAMCA) by following increase in fluorescence upon release of7-amino-4-methyl coumarin (λ_(EX)=355 nm, (λ_(EM)=460 nm). Analytical.Biochemistry (2005). 343, 143-51

Assays are performed on either cell lysate or microsome fractionsprepared as described or in whole cell format employing either thefluorescent substrate AAMCA (Cayman chemical, Ann Arbor, Mich.,) or³H-anandmaide ([ETHANOLAMINE-1-3H]American Radiolabeled Chemicals; 1mCi/ml). The cell lysate or microsome assay is performed in Costar blackwall, clear bottom plates by adding FAAH_CHO (whole cell, cell lysate ormicrosome) in assay buffer (50 mM Phosphate, pH 8.0, 1 mM EDTA, 200 mMKCl, 0.2% glycerol, 0.1% fatty acid free BSA) to each well, followed byeither DMSO or compound and allowed to incubate at 22-25° C. for fifteenminutes. AAMCA substrate was used to achieve a final concentration of 1μM and reaction allowed to proceed at room temperature for 1-3 hours.Fluorescent release as a measure of FAAH activity was monitored byreading the plate in a CytoFluor Multiplate Reader (Ex: 360/40 nM; Em:460/40 nM). Whole cell assay is conducted with cells harvested afterrinsing tissue culture flasks three times with Ca⁺⁺Mg⁺⁺ free PBS,incubating for 10 min in Enzyme free dissociation media and centrifugingfor 5 minutes at 1,000 rpm in table top centrifuge. Cells areresuspended in assay buffer at desired cell number in (4×10⁴ cells/assayin 96-well format; 1×10⁴ cells/assay in 384-well format) and assayed asdescribed.

Alternatively, assays are performed using anandamide [ethanolamine1-.sup.3H] (specific activity of 10 Ci/mmol) diluted with coldanandamide to achieve a final assay concentration of 1 μM anandamide(˜50,000 cpm). Enzyme (CHO cell lysate, brain or liver homogenate) isincubated in assay buffer (50 mM Phosphate, pH 8.0, 1 mM EDTA, 200 mMKCl, 0.2% glycerol, 0.1% fatty acid free BSA) with inhibitor at 25° C.for 30 minutes. The reaction was terminated by addition of 2 volumes ofchloroform:methanol (1:1) and mixed by vortexing. Following acentrifugation step, 2000 rpm for 10 min. at room temperature, theaqueous phase containing the released ³H-ethanolamide was recovered andquantitated by liquid scintillation as a reflection of FAAH enzymeactivity.

-   Ramarao M. K., et al. A fluorescence-based assay for fatty acid    amide hydrolase compatible with high-throughput screening. Anal    Biochem. 343:143-51 (2005)-   Wilson S. J. et 1. A high-throughput-compatible assay for    determining the activity of fatty acid amide hydrolase. Anal    Biochem. 318:270-5 (2003).

Each of Examples 1 through 56 was tested and found to demonstratebiological activity. Results for specific Examples are provided below.Each of Examples 1 through 56 was found to have and IC50 of 3 μM orlower in these assays.

Human Lysate Human whole cell Rat whole cell Example IC50 (nM) IC50 (nM)IC50 (nM) Ex 3 23 71 44 Ex 12 19 25 13 Ex 19 38 78 18 Ex 20 43 59 29 Ex35 27 37 21 Ex 37 13 40 15 Ex 46 17 39 10 Ex 48 9 77 8 Ex 51 26 148 107Ex 56 15 114 16

Preparation of the Compounds of the Invention.

The compounds of the present invention can be prepared according to theprocedures denoted in the following reaction Schemes and Examples ormodifications thereof using readily available starting materials,reagents, and conventional procedures thereof well-known to a practionerof ordinary skill in the art of synthetic organic chemistry. Specificdefinitions of variables in the Schemes are given for illustrativepurposes only and are not intended to limit the procedures described.

Intermediate 1

2-(4-Fluorophenyl)-1,3-oxazol-4-yl trifluoromethanesulfonate

The title compound was prepared using the procedure described byLangille, N. F.; Dakin, L. A.; Panek, J. S. Org. Lett. 2002, 4, 2485.

Intermediate 2

2-(3-Fluorophenyl)-1,3-oxazol-4-yl trifluoromethanesulfonate

The title compound was prepared using the procedure described byLangille, N. F.; Dakin, L. A.; Panek, J. S. Org. Lett. 2002, 4, 2485.

Intermediate 3

2-(3,5-Difluorophenyl-1,3-oxazol-4-yl trifluoromethanesulfonate

The title compound was prepared using the procedure described byLangille, N. F.; Dakin, L. A.; Panek, J. S. Org. Lett. 2002, 4, 2485.

Intermediate 4

2-(3,4-Difluorophenyl)-1,3-oxazol-4-yl trifluoromethanesulfonate

The title compound was prepared using the procedure described byLangille, N. F.; Dakin, L. A.; Panck, J. S. Org. Lett. 2002, 4, 2485.

Intermediate 5

2-(4-Chlorophenyl-1,3-oxazol-4-yl trifluoromethanesulfonate

The title compound was prepared using the procedure described byLangille, N. F.; Dakin, L. A.; Panek, J. S. Org. Lett. 2002, 4, 2485.

Intermediate 6

2-(3-Chloro-4-fluorophenyl)-1,3-oxazol-4-yl trifluoromethanesulfonate

The title compound was prepared using the procedure described byLangille, N. F.; Dakin, L. A.; Panek, J. S. Org. Lett. 2002, 4, 2485.

Intermediate 7

2-(4-Chloro-3-fluorophenyl)-1,3-oxazol-4-yl trifluoromethanesulfonate

The title compound was prepared using the procedure described byLangille, N. F.; Dakin, L. A.; Panek, J. S. Org. Lett. 2002, 4, 2485.

Intermediate 8

2-(4-Fluoro-2-methylphenyl)-1,3-oxazol-4-yl trifluoromethanesulfonate

The title compound was prepared using the procedure described byLangille, N. F.; Dakin, L. A.; Panek, J. S. Org. Lett. 2002, 4, 2485.

Intermediate 9

Methyl 5-[2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyrazine-2-carboxylate StepA

A solution of intermediate 1 (2.66 g, 8.55 mmol), bis-pinacolatodiboron(2.60 g, 10.3 mmol), KOAc (1.68 g, 17.1 mmol), and Pd(dppf)Cl₁ (0.70 g,0.86 mmol) in 1,4-dioxane (25 mL) were heated to 140° C. for 30 min.Upon completion of the reaction as judged by TLC analysis, the solutionwas concentrated to dryness and purified on silica gel to afford thecorresponding boronic acid intermediate which was taken on immediately.

Step B

The boronic acid prepared in Step A (1.00 g, 4.80 mmol), methyl5-chloropyrazine-2-carboxylate (1.70 g, 10.0 mmol), Pd(PPh₃)₄ (558 mg,0.48 mmol), K₂CO₃ (2.00 g, 14.5 mmol) were dissolved in toluene (10 mL,)and H₂O (1 mL) and degassed for 5 min. After which, the solution washeated in the microwave reactor to 120° C. for 30 min. Upon completionof the reaction as judged by TLC analysis, the solution was diluted withdist H₂O and extracted with EtOAc. The organic layer was removed, driedover MgSO₄, filtered and concentrated giving rise to an oil. The oil waspurified on silica gel to afford the title compound (290 mg). LC/MS: m/e300.1 (M+H).

Intermediate 10

2-Pyrazinecarboxylic acid,5-[2-(4-fluorophenyl)-5-iodo-4-oxazolyl]-methyl ester

A solution of Intermediate 9 (1.40 g, 4.70 mmol), NIS (1.30 g, 5.60mmol), TFA (0.40 mL) in CH₃CN (100 mL) was stirred at rt for 12 h. Uponcompletion of the reaction, the solution was diluted with sat aq Na₂S₂O₃and extracted with EtOAc. The organic layer was removed, dried overMgSO₄, filtered and concentrated giving rise to an oil. The oil waspurified on silica gel to afford the title compound (684 mg). LC/MS: m/e425.9 (M+H)⁺. ¹H NMR (500 MHz, Acetone-d6): δ 4.01 (s, 3H), 7.41 (t,J=8.8 Hz, 2H), 8.20-8.25 (m, 2H), 9.28 (s, 1H), 9.39 (s, 1H).

Intermediate 11

2-{5-[2-(4-Fluorophenyl)-1,3-oxazol-4-yl]pyridin-2-yl}propan-2-ol

A solution of Intermediate 1 (60 g, 0.20 mol), bis-pinacolatodiboron(500 g, 0.25 mol), KOAc (57.0, 0.58 mol), Pd(dppf)Cl₂ (7.90 g, 9.60mmol), and dppf (5.34 g, 9.60 mmol) in 1,4-dioxane (1.6 L) were heatedto 101° C. for 3 h. Upon completion of the reaction as judged by TLCanalysis, the reaction was allowed to cool to 65° C. At which point,2-(5-bromopyridin-2-yl)propan-2-ol (62.6 g, 0.30 mol) and Pd(PPh₃)₂Cl₂(13.6 g, 0.02 mol) were added followed by dropwise addition of aqueousNa₂CO₃ (193 mL, 0.40 mol, 2 M). The solution was heated to 91° C. for 12h. Upon completion of the reaction as judged by LC/MS analysis, thesolution was diluted with dist H₂O and extracted with EtOAc (2×). Thecombined organic layers were removed, dried over MgSO₄, filtered andconcentrated giving rise to an oil. The oil was purified on silica gelto give afford the title compound (38.50 g). LC/MS: m/e 299.1 (M+H).

Intermediate 12

2-{5-[5-Bromo-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyridin-2-yl}propan-2-ol

A solution of Intermediate 11 (38.5 g, 0.13 mol) and NBS (28.0 g, 0.16mol) in CH₂Cl₂ (1340 mL) was stirred at rt for 12 h. Upon completion ofthe reaction, the solution was diluted with sat aq NaS₂O₃ solution. Theorganic layer was removed, dried over MgSO₄, filtered and concentratedgiving rise to an oil. The oil was purified on silica gel to afford thetitle compound (31.97 g). LC/MS: m/e 377.0 (M+H)⁺.

Intermediate 13

4-[2-(4-Fluorophenyl)-1,3-oxazol-4-yl]benzonitrile

A solution of Intermediate 1 (560 mg, 1.80 mol), (4-cyanophenyl)boronicacid (291 mg, 2.00 mmol), K₂CO₃ (497 mg, 3.60 mmol) and Pd(PPh₃)₄ (104mg, 0.09 mmol) in 1,4-dioxane (10 mL) were heated to 110° C. for 20 min.Upon completion of the reaction as judged by TLC analysis, the reactionwas concentrated to dryness and purified on silica gel to afford thetitle compound (470 mg). LC/MS: m/e 265.2 (M+H).

Intermediate 14

4-[2-(4-Fluorophenyl)-5-iodo-1,3-oxazol-4-yl]benzonitrile

A solution of Intermediate 13 (476 mg, 1.80 mmol), NIS (608 mg, 2.70mmol), TFA (0.14 mL) in CH₂Cl₂ (15 mL) was stirred at rt for 12 h. Uponcompletion of the reaction, the solution was diluted with sat aq Na₂S₂O₃and extracted with EtOAc. The organic layer was removed, dried overMgSO₄, filtered and concentrated giving rise to an oil. The oil waspurified on silica gel to afford the title compound (700 mg). LC/MS: m/e391.1 (M+H)⁺. ¹H NMR (500 MHz, Acetone-d6): δ 7.41 (t, 2H), 7.94 (d,2H), 8.20 (m, 2H), 8.36 (d, 2H).

Intermediate 15

2-{5-[2-(4-Chlorophenyl)-1,3-oxazol-4-yl]pyridin-2-yl}propan-2-ol

The target compound was prepared in an analogous manner to Intermediate11 except that Intermediate 5 was coupled with2-(5-bromopyridin-2-yl)propan-2-ol (XXX g). LC/MS: m/e 315.1 (M+H).

Intermediate 16

4-{4-[6-(1-Hydroxy-1-methylethyl)pyridin-3-yl]-1,3-oxazol-2-yl}benzonitrile

A solution of Intermediate 15 (200 mg, 0.60 mmol), Pd₂dba₃ (93 mg, 0.10mmol), S-Phos (104 mg, 0.25 mmol) and Zn(CN)₂ (112 mg, 0.90 mmol) in 10mL of 99:1 v:v DMF:H₂O were heated to 180° C. for 30 min in themicrowave reactor. Upon completion of the reaction as judged by LC/MSanalysis, the solution was diluted with dist H₂O and extracted withEtOAc (2×). The combined organic layers were removed, dried over MgSO₄,filtered and concentrated giving rise to an oil. The oil was purified onsilica gel to afford the title compound (194 mg). LC/MS: m/e 306.1(M+H).

Intermediate 17

4-{5-Bromo-4-[6-(1-hydroxy-1-methylethyl)pyridin-3-yl]-1,3-oxazol-2-yl}benzonitrile

A solution of Intermediate 16 (476 mg, 1.80 mmol) and NBS (608 mg, 2.70mmol) in CH₂Cl₂ (15 mL) was stirred at rt for 12 h. Upon completion ofthe reaction, the solution was diluted with sat aq Na₂S₂O₃ and extractedwith EtOAc. The organic layer was removed, dried over MgSO₄, filteredand concentrated giving rise to an oil. The oil was purified on silicagel to afford the title compound (43.7 mg). LC/MS: m/e 384.0 (M+H)⁺.

Example 1

Methyl-5-[5-[(5-chloropyridin-2-yl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyrazine-2-carboxyate

A solution of 5-chloropyridine-2-thiol (305 mg, 2.10 mmol) dissolved in18 mL of NMP was treated with NaH (84 mg, 2.10 mmol). The resultingsolution was stirred for 30 min at rt before Intermediate 10 (684 mg,1.60 mmol) and CuI (306 mg, 1.60 mmol) were added to the solution. Theresulting dark solution was heated to 120° C. for 2 h. After whichpoint, the solution was poured into a rapidly stirred solution of 9:1NH₄Cl:NH₄OH and EtOAc. Upon clarification of the organic layer, removalof the organic layer was followed by drying over MgSO₄, filtration andconcentration giving rise to an oil. The oil was purified on silica gelto afford the title compound (410 mg). LC/MS: m/e 443.0 (M+H)⁺. ¹H NMR(500 MHz, Acetone-d6): δ 4.01 (s, 3H), 7.37-7.41 (m, 2H), 8.04 (m, 2H),8.70 (s, 1H), 9.28 (d, J=1.5 Hz, 1H), 9.44 (d, J=1.0 Hz, 1H).

The compounds in Table 1 were prepared from the appropriate startingmaterials using the procedure for Example 1.

TABLE 1

LCMS: found Example R₂ R₃ m/e (M + H) 2

442.9

Example 3

2-{5-[5-[(5-Chloropyridin-2-yl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyrazin-2-yl}propan-2-o

A solution ofmethyl-5-[5-[(5-chloropyridin-2-yl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyrazine-2-carboxylate(Example 1) (410 mg, 0.93 mmol) in THF (20 mL) was treated withmethylmagnesium bromide (3.1 mL, 9.3 mmol, 3.0 M in THF) at rt. Uponcompletion of the reaction as judged by TLC analysis, the solution wasdiluted with saturated aq NH₄Cl solution and extracted with EtOAc. Theorganic layer was removed, dried over MgSO₄, filtered and concentratedgiving rise to an oil. The oil was purified on silica gel to afford thetitle compound (90 mg). LC/MS: m/e 442.9 (M+H)⁺. ¹H NMR (500 MHz,Acetone-d6): δ 1.58 (s, 6H), 4.58 (s, 1H), 7.42 (m, 3H), 7.76 (dd,J=2.6, 8.8 Hz, 2H), 8.32 (m, 2H), 8.43 (d, J=2.7 Hz, 1H), 8.96 (s, 1H),9.19 (s, 1H).

The compounds in Table 2 were prepared from the appropriate startingmaterials using the procedure for Example 3.

TABLE 2

LCMS: found Example R₂ R₃ m/e (M + H) 4

441.9 5

438.2 6

441.9 7

438.0 8

442.9

Example 9

2-[5-[(4-Chlorophenyl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]-5-methylpyrazin

A solution ofmethyl-5-[5-[(4-chlorophenyl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyrazine-2-carboxylate(Example 1) (24 mg, 0.05 mmol) in THF (5 mL) was treated withmethylmagnesium bromide (0.2 mL, 0.5 mmol, 3.0 M in THF) at rt. Uponcompletion of the reaction as judged by TLC analysis, the solution wasdiluted with saturated aq NH₄Cl solution and extracted with EtOAc. Theorganic layer was removed, dried over MgSO₄, filtered and concentratedgiving rise to an oil. The oil was purified on silica gel to afford thetitle compound (6.3 mg). LC/MS: m/e 397.0 (M+H)⁺. ¹H NMR (500 MHz,Acetone-d6): δ 2.55 (s, 3H), 7.46 (m, 5H), 8.06 (m, 2H), 8.50 (s, 1H),8.55 (s, 1H), 9.10 (d, J=1.1 Hz, 1H).

The compounds in Table 3 were prepared from the appropriate startingmaterials using the procedure for Example 9.

TABLE 3

LCMS: found Example R₂ R₃ m/e (M + H) 10

394.1 11

397.9

Example 12

2-{5-[5-[(5-Chloropyridin-2-yl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyridin-2-yl}propan-2-ol

A solution of 5-chloropyridine-2-thiol (27.3 g, 0.20 mol) dissolved in200 mL of NMP was treated with NaH (7.7 g, 0.20 mol). The resultingsolution was stirred for 30 min at rt before Intermediate 12 (31.9 g,0.08 mol) dissolved in 200 mL of NMP was added by addition funnel.Lastly, CuI (16.3 g, 0.08 mol) was added to the solution. The resultingdark solution was heated to 120° C. for 2 h. After which point, thesolution was cooled to rt. Once at rt, the solution poured into arapidly stirred solution of 9:1 NH₄Cl:NH₄OH and EtOAc. Uponclarification, the organic layer was removed followed by drying overMgSO₄, filtration and concentration giving rise to an oil. The oil waspurified on silica gel to afford the title compound (31.87 g). LC/MS:m/e 442.1 (M+H)⁺. ¹H NMR (500 MHz, Acetone-d6): δ 1.76 (s, 6H), 5.01 (s,1H), 7.40 (m, 3H), 7.80 (m, 2H), 8.25 (m, 2H), 8.44 (dd, J=2.3, 8.2 Hz,1H), 8.44 (d, J=2.3 Hz, 1H), 9.20 (d, J=1.4 Hz, 1H).

Example 12^(a)

2-{5-[5-[(5-Chloropyridin-2-yl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyridin-2-yl}propan-2-ol,hydrogen chloride salt

A solution of Example 12 (138 mg, 0.31 mmol) was taken up in 7 mL ofIPAC and heated to 65° C. Upon complete dissolution, Hcl (78 μl, 0.31mmol, 4N in dioxane) was added dropwise. The resulting slurry wasmaintained at 65° C. for 2 h before being allowed to cool to rt. Theslurry was filtered giving rise to a white solid (100.7 mg). LC/MS: m/e442.1 (M+H)⁺

The compounds in Table 4 were prepared from the appropriate startingmaterials using the procedure for Example 12.

TABLE 4

LCMS: found Example R₂ R₃ m/e (M + H) 13

441.0 14

437.0 15

443.0 16

459.0 17

443.0 18

445.0 19

426.1 20

442.9 21

438.1 22

427.0 23

439.0 24

439.0 25

422.1 26

448.1 27

461.3 28

459.3 29

440.9 30

437.0 31

442.0 32

459.9 33

455.0 34

459.0 35

460.0 36

461.3 37

456.6 38

457.9 39

442.0 40

459.0 41

475.0 42

476.0 43

475.0 44

476.0

Example 45

2-{6-[5-[(5-Chloropyridin-2-yl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyridin-3-yl}propan-2-ol

The title compound was prepared following the procedure described forExample 12, substituting 2-(5-bromopyridin-2-yl)propan-2-ol with2-(6-bromopyridin-3-yl)propan-2-ol. The oil was purified on silica gelto afford the title compound (74 mg). LC/MS: m/e 442.0 (M+H)⁺. ¹H NMR(500 MHz, Acetone-d6): δ 1.59 (s, 6H), 4.42 (s, 1H), 7.36 (m, 3H), 7.75(dd, J=2.6, 8.6 Hz, 1H), 8.06 (m, 2H), 8.21 (m, 2H), 8.43 (d, J=2.5 Hz,1H), 8.77 (s, 1H).

The compounds in Table 5 were prepared from the appropriate startingmaterials using the procedure for Example 45.

TABLE 5

LCMS: found Example R₂ R₃ m/e (M + H) 46

441.0

Example 47

4-[5-[(4-Chlorophenyl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]benzonitrile

A solution of 4-chlorobenzenethiol (389 mg, 2.70 mmol) dissolved in 5 mLof NMP was treated with NaH (108 mg, 2.70 mmol). The resulting solutionwas stirred for 30 min at rt before Intermediate 14 (700 mg, 1.80 mmol)and CuI (342 mg, 1.80 mmol) were added to the solution. The resultingdark solution was heated to 120° C. for 2 h. After which point, thesolution was poured into a rapidly stirred solution of 9:1 NH₄Cl:NH₄OHand EtOAc. Upon clarification of the organic layer, removal of theorganic layer was followed by drying over MgSO₄, filtration andconcentration giving rise to an oil. The oil was purified on silica gelto afford the title compound. LC/MS: m/e 407.8 (M+H)⁺.

Example 48

3-{4-[5-[(4-Chlorophenyl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]phenyl}-1,2,4-oxadiazole

To Example 47 (100 mg, 0.25 mmol) in 10 mL EtOH was added 1.0 mL of 50wt % aqueous NH₂OH and 15 mg of K₂CO₃. The reaction was heated to 120°C. for 5 min via microwave irradiation. The reaction mixture wasconcentrated to dryness and the residue was dissolved in 5 mLtriethylorthoformate, 10 mL EtOH and 1 mL of TFA. The reaction washeated to 100° C. for 10 min via microwave irradiation. The volatileswere removed and the residue was purified on silica gel to afford thetitle compound (111 mg). LC/MS: m/e 450.0 (M+H)⁺. ¹H NMR (500 MHz,Acetone-d6): δ 7.37-7.41 (m, 6H), 8.21 (m, 4H), 8.40 (m, 2H), 9.41 (s,1H).

Example 49

4-{5-[(5-Chloropyridin-2-yl)thio]-4-[6-(1-hydroxy-1-methylethyl)pyridin-3-yl]-1,3-oxazol-2-yl}benzonitrile

The title compound was prepared following the procedure described forExample 12 using Intermediate 17 (42 mg, 0.10 mmol) and5-chloropyridine-2-thiol (35.0 mg, 0.24 mmol). The oil was purified onsilica gel to afford the title compound (44.6 mg). LC/MS: m/e 449.0(M+H)⁺. ¹H NMR (500 MHz, Acetone-d6): δ 1.53 (s, 6H), 4.61 (s, 1H), 7.44(d, J=8.7 Hz, 1H), 7.80 (m, 2H), 8.03 (d, J=8.5 Hz, 2H), 8.36 (d, J=8.5Hz, 2H), 8.43 (d, J=2.5 Hz, 1H), 8.45 (t, J=2.5 Hz, 1H), 9.20 (d, J=2.1Hz, 1H).

Example 50

2-(5-{5-[(4-chlorophenyl)thio]-2-pyridin-2-yl-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol,trifluoroacetic acid salt

2-bromo-1-(6-bromopyridin-3-yl)ethanone Step A

To a solution of 1-(6-bromo-pyridin-3-yl)-ethanone (20.3 g, 101 mmol)and aluminum chloride (200 mg, 1.5 mmol) in chloroform (288 mL) wasadded bromine (5.23 mL, 101 mmol). The mixture was stirred at rt for 16h. Upon completion of the reaction as judged by LC/MS analysis, thesolution was diluted with sat aq NaHCO₃ and extracted with DCM. Theorganic layer was removed, dried over MgSO₄, filtered and concentratedgiving rise to 31 g 2-bromo-1-(6-bromopyridin-3-yl)ethanone, which wastaken on immediately. LC/MS: m/e 277.9 (M+H).

2-bromo-5-(2-pyridin-2-yl-1,3-oxazole-4-yl)pyridine Step B

A mixture of 2-bromo-1-(6-bromopyridin-3-yl)ethanone from Step A (2.3 g,8.25 mmol) and pyridine-2-carboxamide (1 g, 8.25 mmol) was melted at85°. Heating was continued until the mixture reached 140° at which pointthe product solidified. Ice, EtOAc and sat aq NaHCO₃ were added. Theaqueous layer was then back extracted with EtOAc/THF (3:1).

Pooled organics were dried over MgSO₄, filtered, concentrated, andpurified on silica gel to afford 250 mg (10% yield) of2-bromo-5-(2-pyridin-2-yl-1,3-oxazole-4-yl)pyridine. LC/MS: m/e 302.0(M+H).

methyl 5-(2-pyridin-2-yl-1,3-oxazol-4-yl)pyridine-2-carboxylate Step C

A mixture of 2-bromo-5-(2-pyridin-2-yl-1,3-oxazole-4-yl)pyridine fromStep B (250 mg, 0.827 mmol), dppf (92 mg, 0.166 mmol), Pd(OAc)₂ (19 mg,0.0826 mmol), TEA (0.137 mL, 0.993 mmol) in MeOH (1.4 mL) and DMF (1.4mL) was bubbled with carbon monoxide for 15 min. The mixture was thenplaced under a balloon filled with carbon monoxide and stirred at rt for0.5 h before heating to 75° for 16 h. Upon completion of the reaction asjudged by LCMS analysis, the solution was diluted with dist H₂O andextracted with EtOAc. The organic layer was removed, dried over MgSO₄,filtered through a pad of Celite, concentrated, and purified on silicagel giving rise to 200 mg (86% yield) of methyl5-(2-pyridin-2-yl-1,3-oxazol-4-yl)pyridine-2-carboxylate. LCMS: m/e282.1 (M+H).

2-[5-(2-pyridin-2-yl-1,3-oxazol-4-yl)pyridin-2-yl]propan-2-ol Step D

To a solution of methyl5-(2-pyridin-2-yl-1,3-oxazol-4-yl)pyridine-2-carboxylate from Step C.(75 mg, 0.267 mmol) in THF (1 mL) at 0° was added a 3 M solution ofmethylmagnesium bromide in diethyl ether (0.533 mL, 1.6 mmol). The icebath was removed and the reaction mixture was stirred for 1 h under anatmosphere of nitrogen. Upon completion of the reaction as judged byLCMS analysis, the solution was diluted with sat aq NH₄Cl and extractedwith EtOAc. The organic layer was removed, dried over MgSO₄, filteredand concentrated giving rise to2-[5-(2-pyridin-2-yl-1,3-oxazol-4-yl)pyridin-2-yl]propan-2-ol, which wastaken on immediately. LC/MS: m/e 282.1 (M+H).

2-[5-(5-bromo-2-pyridin-2-yl-1,3-oxazol-4-yl)pyridin-2-yl]propan-2-olStep E

To a solution of2-[5-(2-pyridin-2-yl-1,3-oxazol-4-yl)pyridin-2-yl]propan-2-ol from StepD (75 mg, 0.267 mmol) in DCM (1 mL) was added NBS (62 mg, 0.347 mmol).The reaction mixture was stirred at rt for 16 h. Water was added and themixture extracted with DCM. The organics were dried (MgSO₄), andconcentrated to afford2-[5-(5-bromo-2-pyridin-2-yl-1,3-oxazol-4-yl)pyridin-2-yl]propan-2-ol,which was used without further purification LCMS: m/z 360.0 (M+H)⁺.

Step F.

To a solution of 4-chloro thiophenol (38 mg, 0.264 mmol) in NMP (0.5 mL)was added NaH (11 mg, 0.264 mmol) and stirred at rt for 0.5 h under anatmosphere of nitrogen. To the resulting sodium salt was added asolution of2-[5-(5-bromo-2-pyridin-2-yl-1,3-oxazol-4-yl)pyridin-2-yl]propan-2-olfrom Step E (38 mg, 0.105 mmol) in NMP (0.5 mL) followed by CuI (20 mg,0.105 mmol). The mixture was then heated at 120° for 2 h under anatmosphere of nitrogen. Saturated aqueous ammonium chloride (4.5 mL) andammonium hydroxide (0.5 mL) were added and the mixture stirred at rt for0.5 h. The mixture was extracted 3 times with EtOAc. Combined organicswere dried (MgSO₄), concentrated, and purified by reverse phase HPLC toafford 20 mg (35% yield over 3 steps) of the title compound as the TFAsalt. LCMS: m/z 424.1 (M+H)⁺. ¹H NMR (500 MHz, CO(CD₃)₂: δ 9.25 (1H, s),8.75 (1H, m), 8.50 (1H, m), 8.32 (1H, d), 8.06 (1H, m), 7.82 (1H, m),7.60 (1H, m), 7.43 (4H, br), 1.55 (6H, s).

Example 51

2-(5-{5-[(5-chloropyridin-2-yl)thio]-2-pyridin-2-yl-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol,trifluoroacetic acid salt

To a solution of 5-chloropyridine-2-thiol (38 mg, 0.264 mmol) in NMP(0.5 mL) was added NaH (11 mg, 0.264 mmol) and stirred at rt for 0.5 hunder an atmosphere of nitrogen. To the resulting sodium salt was addeda solution of2-[5-(5-bromo-2-pyridin-2-yl-1,3-oxazol-4-yl)pyridin-2-yl]propan-2-ol(38 mg, 0.105 mmol) in NMP (0.5 mL) followed by CuI (20 mg, 0.105 mmol).The mixture was then heated at 120° for 2 h under an atmosphere ofnitrogen. Saturated aqueous ammonium chloride (4.5 mL) and ammoniumhydroxide (0.5 mL) were added and the mixture stirred at rt for 0.5 h.The mixture was extracted 3 times with EtOAc. Combined organics weredried (MgSO₄), concentrated, and purified by reverse phase HPLC toafford 18 mg (32% yield over 3 steps) the title compound as the TFAsalt. LCMS: m/z 425.1 (M+H)⁺. ¹H NMR (500 MHz, CO(CD₃)₂: δ 9.22 (1H, s),8.77 (1H, s), 8.55 (2H, br), 8.34 (1H, m), 8.07 (1H, m), 7.81 (2H, br),7.61 (1H, m), 7.42 (1H, d) 1.54 (6H, s).

Example 52

5-[(4-chlorophenyl)-thio]-4-(4-cyanophenyl)-2-phenyl-1,3-oxazole

4-(2-phenyl-1,3-oxazol-4-yl)benzonitrile Step A

The mixture of the 2-bromo-1-(4-cyanophenyl)ethanone (4 g, 17.85 mmol)and benzamide (5.41 g, 44.6 mmol) was heated to 135° C. for 3 hours.Then the reaction mixture was cooled, and partitioned between diethylether and water. The aqueous layer was extracted with ether twice, andthe combined organic layers were washed with 1N NaOH, 1N HCl, water, andbrine, dried over MgSO₄. After concentration, the solid residue wasdissolved in CHCl3. The insoluable solid was filtered through a fritsfunnel and discarded. The CHCl3 solution was filtered through a pad ofsilica and evaporate to dryness to give 2.9 g (66% yield) of4-(2-phenyl-1,3-oxazol-4-yl)benzonitrile. LCMS: m/z 247.1 (M+H)⁺.

4-(5-iodo-2-phenyl-1,3-oxazol-4-yl)benzonitrile Step B

The product of Step A (140 mg, 0.57 mmol) was dissolved in 2 mL ofchloroform, to which was added NIS (282 mg, 1.35 mmol) and 2 drops ofTFA. After stirring at rt for two days, the reaction was diluted withdichloromethane, washed with aq NaHCO₃, aq Na₂S₂O₃, water, and brine.The organic layer was dried over MgSO₄, filtered, and concentrated togive 186 mg (88% yield) of4-(5-iodo-2-phenyl-1,3-oxazol-4-yl)benzonitrile. LCMS: m/z 373.0 (M+H)⁺.

Step C.

CuI (4.8 mg, 0.025 mmol), K₂CO₃ (138 mg, 1 mmol), the product of Step B(186 mg, 0.5 mmol), and 4-chlorobenzenethiol (72 mg, 0.5 mmol) wereadded to a flask, which was evacuated and backfilled with N₂ (3 cycles).2-Propanol (2 mL) and ethylene glycol (0.056 mL, 1 mmol) were added bysyringe at rt. The reaction mixture was heated at 80° C. for 18 hours.Then the reaction was diluted with EtOAc, filtered, concentrated, andthe residue was subject to silica column (0-20% EtOAc in hexanes) togive the title compound. 1H NMR (500 MHz, (CDCl₃): 8.38 (d, 2H), 8.19(d, 2H), 7.78 (d, 2H), 7.57 (m, 3H), 7.31 (d, 2H), 7.25 (d, 2H). LCMS:m/z 389.0 (M+H)⁺.

Example 53

3-(4-{5-[(4-Chlorophenyl)thio]-2-phenyl-1,3oxazol-4-yl}phenyl)-1,2,4oxadiazole

To 3-(4-{5-[(4-chlorophenyl)thio]-2-phenyl-1,3oxazol-4-yl}benzonitrile(30 mg, 0.075 mmol) in 2 mL EtOH was added 0.25 mL of 50% aqueous NH₂OHand catalytic amount of K₂CO₃. The reaction was heated at 120° C. for 1h via microwave irradiation. The reaction mixture was concentrated todryness and the residue was dissolved in 5 mL triethylorthoformate. Acatalytic amount of TFA was added, and the reaction was heated at 130°C. for 3 h. The volatiles were removed and the residue was purified byreverse phase HPLC to afford 12 mg (37% yield) of the title compound:m/z 432.1 (M+H)⁺. ¹H NMR (500 MHz, CDCl₃: 8.8 (1H, s), 8.39 (2H, d),8.21 (2H, d), 8.19 (1H, m), 7.59 (4H, br), 7.24 (4H, br).

Example 54

2-(4-{5-[(4-Chlorophenyl)thio]-2-phenyl-1.3oxazol-4-yl}phenyl)-1,3,4oxadiazole

4-{5-[(4-chlorophenyl)thio]-2-phenyl-1,3-oxazol-4-yl}benzoic acid Step A

A solution of3-(4-{5-[(4-chlorophenyl)thio]-2-phenyl-1,3oxazol-4-yl}benzonitrile (30mg, 0.077 mmol) in ethanol (1 mL) and 2N NaOH (1 mL) was heated toreflux for 16 h. EtOAc was added followed by saturated aqueous ammoniumchloride. The organics were dried (MgSO₄) and concentrated to afford4-{5-[(4-chlorophenyl)thio]-2-phenyl-1,3,-oxazol-4-yl}benzoic acid,which was used with out further purification. LCMS: m/z 407.1 (M+H)⁺.

methyl 4-{5-[(4-chlorophenyl)thio]-2-phenyl-1,3-oxazol-4-yl}benzoateStep B

4-{5-[(4-chlorophenyl)thio]-2-phenyl-1,3,-oxazol-4-yl}benzoic acid fromStep A (32 mg, 0.077 mmol) was dissolved in MeOH (0.5 mL) and DCM (0.5mL). Trimethylsilyl diazomethane (2.0 M in ether) was slowly added at 0°C. until a yellow color persisted. The volatiles were evaporated to givemethyl 4-{5-[(4-chlorophenyl)thio]-2-phenyl-1,3,-oxazol-4-yl}benzoatewhich was used without further purification. LCMS: m/z 421.1 (M+H)⁺.

4-{5-[(4-chlorophenyl)thio]-2-phenyl-1,3-oxazol-4-yl}benzohydrazide StepC.

Methyl 4-{5-[(4-chlorophenyl)thio]-2-phenyl-1,3,-oxazol-4-yl}benzoatefrom Step B (33 mg, 0.077 mmol) was suspended in 1 mL of EtOH and 0.5 mLof anhydrous hydrazine, and heated to reflux for 2 h. EtOAc was addedand washed with water 3 times. The organics were dried (MgSO₄), andconcentrated to afford4-{5-[(4-chlorophenyl)thio]-2-phenyl-1,3,-oxazol-4-yl}benzohydrazidewhich was used with out further purification. LCMS: m/z 421.1 (M+H)⁺.

Step D

4-{5-[(4-chlorophenyl)thio]-2-phenyl-1,3,-oxazol-4-yl}benzohydrazidefrom Step C (33 mg, 0.077 mmol) was dissolved in 5 mLtriethylorthoformate. A catalytic amount of TFA was added and thereaction was heated at 130° C. for 2 h. The volatiles were removed andthe residue was purified by reverse phase HPLC to afford 12 mg (36% over4 steps) of the title compound2-(4-{5-[(4-chlorophenyl)thio]-2-phenyl-1,3oxazol-4-yl}phenyl)-1,3,4-oxadiazole.LCMS: m/z 432.1 (M+H)⁺. ¹H NMR (500 MHz, CDCl₃: δ 8.55 (1H, s), 8.40(2H, d), 8.19 (4H, br), 7.55 (3H, br), 7.30 (4H, br).

Example 55

5-[(4-chlorophenyl)thio]-4-[4-(methylsulfonylphenyl-2-phenyl]-1,3-oxazole

4-[4-(methylsulfonyl)phenyl]-2-phenyl-1,3-oxazole Step A

The mixture of the 2-bromo-1-[4-(methylsulfonyl)phenyl]ethanone (2 g,7.2 mmol) and benzamide (0.87 g, 7.2 mmol) was heated to 140˜180° C. for4 hours. When TLC showed that the reaction had completed, the mixturewas cooled, and partitioned between EtOAc and water. The aqueous layerwas extracted with EtOAc twice, and the combined organic layers werewashed with water and brine, dried over MgSO₄. After concentration, theresidue was purified by column (eluted by PE:EA=10:1) to afford 0.6 g(yield 30%) of 4-[4-(methylsulfonyl)phenyl]-2-phenyl-1,3-oxazole.

5-bromo-4-[4-(methylsulfonyl)phenyl]-2-phenyl-1,3-oxazole Step B

To a solution of Step A product (0.7 g, 2.34 mmol) in AcOH (20 ml) andCHCl₃ (30 ml) was added dropwise Br₂ (0.41 g) at rt, and the mixture wasstirred for 2 hours. The reaction mixture was poured into water, andextracted with EtOAc three times. The combined organic layers werewashed with aqueous NaHCO₃ and brine, dried over Na₂SO₄. Afterconcentration, the residue was purified by column (PE:EA=4:1) to afford0.7 g (yield 80%) of5-bromo-4-[4-(methylsulfonyl)phenyl]-2-phenyl-1,3-oxazole.

Step C

To a solution of Step B product (0.2 g, 0.53 mmol) and4-chlorbenzenethiol (0.076 g, 0.53 mmol) in ethanol was added KOH (34mg, 0.6 mmol) at rt under N₂, then the mixture was heated to refluxovernight. After cooling, the precipitate was collected by suction, andthe filter cake was washed with ethanol. After drying, 200 mg (yield80%) of the title compound was obtained. ¹H-NMR (400 MHz, DMSO) δ 8.30(d, 2H, Ar—H), 8.06 (m, 4H, Ar—H), 7.60 (m, 3H, Ar—H), 7.40 (m, 4H,Ar—H), 3.26 (s, 3H, CH₃).

Example 56

2-{5-[(4-chlorophenyl)thio]-[4-(methylsulfonyl)phenyl]-1,3-oxazol-2-yl}pyridine

2-{4-[4-(methylsulfonyl)phenyl]-1,3-oxazol-2-yl}pyridin Step A

The mixture of the 2-bromo-1-[4-(methylsulfonyl)phenyl]ethanone (500 mg,1.8 mmol) and pyridine 2-carboxamide (551 mg, 4.51 mmol) was heated to150° C. for 1 hour. Then the reaction mixture was cooled, andpartitioned between ethyl acetate and water. The aqueous layer wasextracted with ethyl acetate twice, and the combined organic layers werewashed with water and brine, dried over MgSO₄. After concentration, thesolid residue was dissolved in methanol and subject to mass-directedHPLC purification to give 21 mg of2-{4-[4-(methylsulfonyl)phenyl]-1,3-oxazol-2-yl}pyridine. LCMS: m/z301.0 (M+H)⁺.

2-{5-iodo-4-[4-(methylsulfonyl)phenyl]-1,3-oxazol-2-yl}pyridine Step B

The product of Step A (20 mg, 0.067 mmol) was dissolved in 1 mL ofchloroform, to which was added NIS (22.5 mg, 0.1 mmol) and 1 drop ofTFA. After stirring at rt for 2 hours, the reaction was diluted withdichloromethane, washed with aq NaHCO₃, aq Na₂S₂O₃, water, and brine.The organic layer was dried over MgSO₄, filtered, and concentrated togive 2-{5-iodo-4-[4-(methylsulfonyl)phenyl]-1,3-oxazol-2-yl}pyridine.LCMS: m/z 427.0 (M+H)⁺.

Step C.

CuI (2 mg, 0.01 mmol), K₂CO₃ (6.5 mg, 0.05 mmol), the product of Step B(10 mg, 0.023 mmol), and 4-chlorobenzenethiol (3.4 mg, 0.023 mmol) wereadded to a flask, which was evacuated and backfilled with N₂ (3 cycles).2-Propanol (0.5 mL) and 0.01 mL of ethylene glycol were added by syringeat rt. The reaction mixture was heated at 80° C. for 18 hours. Then thereaction was diluted with acetonitrile and filtered through Celite. Thefiltrate was subjected to mass-directed HPLC to give the title compound.1H NMR (500 MHz, (CDCl₃): 8.82 (broad s, 1H), 8.47 (d, 2H), 8.23 (d,1H), 8.05 (d, 2H), 7.91 (t, 1H), 7.46 (t, 1H), 7.23 (AB quartct, 4H),3.11 (s, 3H). LCMS: m/z 443.0 (M+H)⁺.

Human Lysate Human whole cell Rat whole cell Example IC50 (nM) IC50 (nM)IC50 (nM) Ex 58 37 112 74 Ex 59 20 67 40 Ex 62 23 41 29 Ex 65 27 29 21Ex 68 15 100 83 Ex 71 10 30 14 Ex 74 8 37 34 Ex 78 28 69 39 Ex 80 35 6725 Ex 90 46 1002 247 Ex 96 17 133 63 Ex 97 20 NA 10 Ex 98 44 222 35 Ex100 161 337 39 Ex 102 12 35 17 Ex 107 24 91 11 Ex 108 5 20 17 Ex 111 1164 24 Ex 119 28 47 20 Ex 122 161 474 146 Ex 123 74 510 286 Ex 124 11 9816 Ex 125 93 2291 680 Ex 131 140 1119 782

Intermediate 18

2-(2,4,5-Trifluorophenyl)-1,3-oxazol-4-yl trifluoromethanesulfonate

The title compound was prepared using the procedure described byLangille, N. F.; Dakin, L. A.; Panek, J. S. Org. Lett. 2002, 4, 2485.

Intermediate 19

2-(4-Methylphenyl)-1,3-oxazol-4-yl trifluoromethanesulfonate

The title compound was prepared using the procedure described byLangille, N. F.; Dakin, L. A.; Panek, J. S. Org. Lett. 2002, 4, 2485.

Intermediate 20

2-Phenyl-1,3-oxazol-4-yl trifluoromethanesulfonate

The title compound was prepared using the procedure described byLangille, N. F.; Dakin, L. A.; Panek, J. S. Org. Lett. 2002, 4, 2485.

Intermediate 21

2-[4-Trifluoromethoxy)phenyl]-1,3-oxazol-4-yltrifluoromethanesulfonate

The title compound was prepared using the procedure described byLangille, N. F.; Dakin, L. A.; Panek, J. S. Org. Lett. 2002, 4, 2485.

Intermediate 22

2-(4-Methoxyphenyl-1,3-oxazol-4-yl trifluoromethanesulfonate

The title compound was prepared using the procedure described byLangille, N. F.; Dakin, L. A.; Panek, J. S. Org. Lett. 2002, 4, 2485.

Intermediate 23

2-(5-Fluoropyridin-3-yl-1,3-oxazol-4-yl trifluoromethanesulfonate

The title compound was prepared using the procedure described byLangille, N. F.; Dakin, L. A.; Panek, J. S. Org. Lett. 2002, 4, 2485.

Intermediate 24

2-Cyclopropyl-1,3-oxazol-4-yl trifluoromethanesulfonate

The title compound was prepared using the procedure described byLangille, N. F.; Dakin, L. A.; Panek, J. S. Org. Lett. 2002, 4, 2485.

Intermediate 25

2-(4-Fluorobenzyl)-1,3-oxazol-4-yl trifluoromethanesulfonate

A. To a stirred solution of 4-fluorophenylacetyl chloride (2.0 g, 12.0mmol) in 25 mL of CH₂Cl₂ was added 1.7 g (12.0 mmol) of silver cyanate.The resulting slurry was stirred for 3 h at rt. After which point, thesolution was filtered through Celite and the filtrate was then taken onto the next step crude.

B. The acyl isocyanate dissolved in DCM was cooled to 0° C. and treatedwith TMS Diazomethane (6.9 mL, 14.0 mmol, 2.0 M solution in Et₂O). Theresulting yellow solution was allowed to warm to rt and stirred for 1 h.Upon completion of the reaction as judged by TLC analysis, the solutionwas concentrated to dryness and purified on silica gel giving 1.3 g ofoxazolidinone intermediate which was taken on directly to triflation.

C. The oxazolidinone (1.3 g, 7 mmol) was treated with Tf₂O (1.7 mL, 10.0mmol) and TEA (2.0 mL, 14.0 mmol) at −78° C. After 1 h, the solution wasdiluted with sat aqueous NaCl solution and allowed to warm to rt. Theorganic layer was removed, dried over MgSO₄, filtered and concentratedto dryness giving rise to an oil. The oil was purified on silica gelgiving rise to the title compound (768 mg). ¹H NMR (500 MHz,Acetone-d6): δ 4.21 (s, 2H), 7.16 (m, 2H), 7.40 (m, 2H), 8.23 (s, 1H).

Intermediate 26

Methyl 4-[2-(4-fluorophenyl)-1,3-oxazol-4-yl]benzoate

A solution of Intermediate 1 (3.09 g, 9.9 mmol),4-[(methoxycarbonyl)phenyl]boronic acid (2.1 g, 12.0 mmol), Pd(dppf)Cl₂,(405 mg, 0.5 mmol), and CsF (3.0 g, 19.9 mmol) were dissolved in dioxane(150 mL) and heated to 100° C. for 12 h. Upon completion of the reactionas judged by TLC analysis, the solution was concentrated to dryness andpurified on silica gel to afford the title compound (2.50 g). LC/MS: m/e395.8 (M+H).

Intermediate 27

A solution of Intermediate 26 (1.06 g, 3.6 mmol) and NBS (952 mg, 5.4mmol) in CH₂Cl₂ (50 mL) was stirred at rt for 12 h. Upon completion ofthe reaction, the solution was diluted with sat aq NaS₂O₃ solution. Theorganic layer was removed, dried over MgSO₄, filtered and concentratedgiving rise to an oil. The oil was purified on silica gel to afford thetitle compound (1.01 g). LC/MS: m/e 375.8 (M+H)⁺.

Intermediate 28

2-(4-Fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-1,3-oxazole

The target compound was prepared in an analogous manner to Intermediate26 except that Intermediate 1 was coupled with[4-(methylsulfonyl)phenyl]boronic acid. LC/MS: m/e 318.1 (M+H).

Intermediate 29

5-Bromo-2-(4-Fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-1,3-oxazole

The target compound was prepared in an analogous manner to Intermediate27. LC/MS: m/e 395.9 (M+H)⁺.

Intermediate 30

5-[2-(4-Fluorophenyl)-1,3-oxazol-4-yl]pyrimidine-2-carbonitrile

The target compound was prepared in an analogous manner to Intermediate11 except that Intermediate 1 was coupled with5-bromopyrimidine-2-carbonitrile. LC/MS: m/e 267.0 (M+H)⁺.

Intermediate 31

5-[5-Bromo-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyrimidine-2-carbonitrile

The target compound was prepared in an analogous manner to Intermediate27. LC/MS: m/e 345.0 (M+H)⁺.

Intermediate 32

5-[2-(4-Fluorophenyl)-1,3-oxazol-4-yl]pyridine-2-carbonitrile

The target compound was prepared in an analogous manner to Intermediate11 except that Intermediate 1 was coupled with5-bromopyridine-2-carbonitrile. LC/MS: m/e 266.0 (M+H).

Intermediate 33

5-[5-Bromo-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyridine-2-carbonitrile

The target compound was prepared in an analogous manner to Intermediate27. LC/MS: m/e 343.9 (M+H)⁺.

Intermediate 34

4-[2-(4-Fluorophenyl)-1,3-oxazol-4-yl]piperidine

A solution of 4-fluorobenzamide (4.54 g, 32.7 mmol) and t-butyl4-(bromoacetyl)-piperidine-1-carboxylate (5.0 g, 16.3 mmol) in DMF (40mL) was heated at 145° C. for 16 h. Upon completion of the reaction, thesolution was allowed to cool to rt and concentrated to a dark oil. Theoil was purified by reverse phase HPLC to afford the title compound (760mg). LC/MS: m/e 247.08 (M+H)⁺.

Intermediate 35

4-[2-(4-Fluorophenyl)-1,3-oxazol-4-yl]-1-(methylsulfonyl)piperidine

To a solution of 4-[2-(4-fluorophenyl)-1,3-oxazol-4-yl]piperidine (220mg, 0.90 mmol) in DCM (20 mL) was treated with DIEA (0.31 mL, 1.8 mmol)and allowed to stir at rt for 15 min. Methanesulfonyl chloride (0.2 mL,2.7 mmol) was slowly added to the solution and the resulting mixture wasstirred at rt for 2 hr. Upon completion of the reaction, DCM (20 mL) andwater (40 mL) was added to the mixture and the two layers werepartitioned. The organic layer was dried with MgSO₄, filtered andconcentrated. The residue was purified by reverse phase HPLC to affordthe title compound (100 mg). LC/MS: m/e 325.2 (M+H)⁺.

Intermediate 36

Methyl2-{5-[2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyridin-2-yl}-2-methylpropanoate

The target compound was prepared in an analogous manner to Intermediate11 except that Intermediate 1 was coupled with methyl2-(5-bromopyridin-2-yl)-2-methylpropanoate (Kodanko, J. J.; Morys, A.J.; Lippard, S. J. Org. Lett. 2005, 7, 4585) LC/MS: m/e 295.4 (M+H)⁺.

Intermediate 37

Methyl2-{5-[5-bromo-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyridin-2-yl}-2-methylpropanoate

The target compound was prepared in an analogous manner to Intermediate27. LC/MS: m/e 373.05 (M+H)⁺.

Intermediate 38

Methyl 5-(1-ethoxyethenyl)pyridine-2-carboxylate

To a solution of methyl 5-bromopyridine-2-carboxylate (25 g, 116 mmol)in dioxane (30 mL) was added Pd(PPh₃)₄ (6.7 g, 5.8 mmol) andtributyl(1-ethoxyvinyl)tin (46 g, 127.0 mmol). The resulting solutionwas heated to reflux under N₂ for 12 h. Upon completion of the reactionas judged by LC/MS analysis, the reaction was diluted with EtOAc, washedwith KF solution (10% aqueous), filtered through Celite, dried overMgSO₄, filtered, concentrated and purified on silica gel to afford thetitle compound (20.4 g). LC/MS: m/e 208.1 (M+H)⁺.

Intermediate 39

Methyl 5-(bromoacetyl)pyridine-2-carboxylate

To a solution of Intermediate 38 (20.3 g, 98.0 mmol) in THF/H₂O (700mL/46 mL) at rt was added NBS (15.0 g, 98.0 mmol) in one portion, Theresulting solution was stirred at rt for 30 min. Upon completion of thereaction as judged by LC/MS analysis, the reaction was concentrated todryness and purified on silica gel to afford the title compound (19.5g). LC/MS: m/e 259.9 (M+H)⁺.

Intermediate 40

Methyl 5-{[(cyclopropylcarbonyl)oxy]acetyl}pyridine-2-carboxylate

The mixture of cyclopropyl carboxylic acid (5.0 g, 58.1 mmol),Intermediate 39 (15.0 g, 58.1 mmol) and K₂CO₃ (9.63 g, 69.7 mmol) in DMF(50 mL) was stirred at rt for 12 h. Upon completion of the reaction asjudged by LC/MS analysis, the reaction was diluted with H₂O and theresulting precipitate was filtered to afford the title compound (8.54g). LC/MS: m/e 263.9 (M+H)⁺.

Intermediate 41

5-(1-Ethoxyethenyl)-2-(methylsulfonyl)pyridine

The target compound was prepared in an analogous manner to Intermediate38 except starting with 5-bromo-2-methylsulphonylpyridine. LC/MS: m/e228.05 (M+H)⁺.

Intermediate 42

2-Bromo-1-[6-(methylsulfonyl)pyridin-3-yl]ethanone

The title compound was prepared in an analogous manner to Intermediate39. LC/MS: m/e 279.76 (M+H)⁺.

Intermediate 43

2-[6-(Methylsulfonyl)pyridin-3-yl]-2-oxoethyl cyclopropanecarboxylate

The title compound was prepared in an analogous manner to Intermediate40. LC/MS: m/e 283.9 (M+H)⁺.

Intermediate 44

Methyl 5-(2-cyclopropyl-1,3-oxazol-4-yl)pyridine-2-carboxylate

To a solution of Intermediate 40 (2.0 g, 7.6 mmol) in p-xylene (130 mL)was added acetamide (2.24 g, 38.0 mmol) and BF₃.OEt₂ (1.9 mL, 15.2mmol). The resulting solution was heated at reflux for 72 h. After whichpoint, the reaction was diluted with sat. NaHCO₃ solution, and extractedwith EtOAc. The organic layer was washed with brine, dried over MgSO₄,filtered, concentrated and purified on silica gel to afford the titlecompound (862 mg). LC/MS: m/e 245.0 (M+H)⁺.

Intermediate 45

Methyl 5-(5-bromo-2-cyclopropyl-1,3-oxazol-4-yl)pyridine-2-carboxylate

The target compound was prepared in an analogous manner to Intermediate27 starting with Intermediate 44. LC/MS: m/e 324.8 (M+H)⁺.

Intermediate 46

2-{6-[2-(4-Fluorophenyl)-1,3-oxazol-4-yl]pyridazin-3-yl}propan-2-ol

The target compound was prepared in an analogous manner to Intermediate11 except that intermediate 1 was coupled with2-(6-chloropyridazin-3-yl)propan-2-ol. LC/MS: m/e 380.0 (M+H)⁺.

Intermediate 47

2-{6-[5-Bromo-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyridazin-3-yl}propan-2-ol

The target compound was prepared in an analogous manner to Intermediate27. LC/MS: m/e 380.0 (M+H)⁺.

Intermediate 48

2-(4-Fluorophenyl)-4-[(trimethylsilyl)ethynyl]-1,3-oxazole

To a solution of Intermediate 1 (2.1 g, 6.8 mmol) in DMF (5 mL) wasadded TMS acetylene (1.9 mL, 13.6 mmol), Pd(PPh₃)Cl₂ (49 mg, 0.07 mmol),CuI (26 mg, 0.14 mmol), LiCl (433 mg, 10.2 mmol) and Diethylamine (9.2mL, 89 mmol). The resulting solution was heated in the microwave reactorfor 5 min at 120° C. After which point, the reaction was diluted withsat. NH₄Cl solution, and extracted with EtOAc. The organic layer waswashed with brine, dried over MgSO₄, filtered, concentrated and purifiedon silica gel to afford the title compound (1.40 g). LC/MS: m/e 262.1(M+H)⁺.

Intermediate 49

4-Ethynyl-2-(4-fluorophenyl)-1,3-oxazole

To a solution of Intermediate 48 (1.4 g, 5.4 mmol) in MeOH (25 mL) wasadded K₂CO₃ (746 mg, 5.4 mmol). The resulting solution was heatedallowed to stir for 12 h. After which point, the solution was dilutedwith H₂O and Et₂O. The organic layer was dried over MgSO₄, filtered,concentrated to afford the title compound (1.01 g). LC/MS: m/e 188.1(M+H)⁺.

Intermediate 50

2-(4-Fluorophenyl)-1,3-oxazole-4-carbonitrile

To a solution of Intermediate 1 (2.1 g, 6.8 mmol) in DMF (15 mL) wasadded Pd(PPh₃)₄ (787 mg, 0.68 mmol), and Zn(CN)₂ (1.20 g, 10.2 mmol).The resulting solution was heated in a microwave reactor for 15 min at120° C. After which point, the reaction was diluted with sat. NH₄Csolution, and extracted with EtOAc. The organic layer was washed withbrine, dried over MgSO₄, filtered, concentrated and purified on silicagel to afford the title compound (260 mg). LC/MS: m/e 189.2 (M+H)⁺.

Intermediate 51

Ethyl 5-[2-(4-fluorophenyl)-1,3-oxazol-4-yl]isoxazole-3-carboxylate

To a stirred solution of Intermediate 49 (1.1 g, 5.9 mmol) in THF/DCM1:1 (40 mL) was added ethyl (2Z)-chloro(hydroxyimino)ethanoate (1.3 g,8.8 mmol) and TEA (2.4 mL, 17.6 mmol). The resulting solution wasstirred for 48 h at rt. After which point, the solution was concentratedand purified on silica gel to afford the title compound (469 mg). LC/MS:m/e 303.0 (M+H)⁺.

Intermediate 52

Ethyl5-[5-bromo-2-(4-fluorophenyl)-1,3-oxazol-4-yl]isoxazole-3-carboxylate

The target compound was prepared in an analogous manner to Intermediate27 starting with Intermediate 51. LC/MS: m/e 382.9 (M+H)⁺

Intermediate 53

Methyl 2-[2-(4-fluorophenyl)-1,3-oxazol-4-yl]-1,3-thiazole-4-carboxylate

The target compound was prepared in an analogous manner to Intermediate11 except that Intermediate 1 was coupled with methyl2-bromothiazole-4-carboxylate. LC/MS: m/e 304.9 (M+H)⁺.

Intermediate 54

Methyl2-[5-bromo-2-(4-fluorophenyl)-1,3-oxazol-4-yl]-1,3-thiazole-4-carboxylate

The target compound was prepared in an analogous manner to Intermediate27 starting with Intermediate 53. LC/MS: m/e 384.9 (M+H)⁺.

Intermediate 55

5-[2-(4-Fluorophenyl)-1,3-oxazol-4-yl]-2-(methylsulfonyl)pyridine

The target compound was prepared in an analogous manner to Intermediate11 except that Intermediate 1 was coupled with2-bromo-5-methylsulphonylpyridine. LC/MS: m/e 318.9 (M+H)⁺

Intermediate 56

5-[5-Bromo-2-(4-fluorophenyl)-1,3-oxazol-4-yl]-2-(methylsulfonyl)pyridine

The target compound was prepared in an analogous manner to Intermediate27 starting with Intermediate 55. LC/MS: m/e 398.9 (M+H)⁺.

Intermediate 57

5-[2-(4-Fluorophenyl)-1,3-oxazol-4-yl]-2-(methylsulfanyl)pyridine

The target compound was prepared in an analogous manner to Intermediate11 except that Intermediate 1 was coupled with5-bromo-2-methylthiopyridine. LC/MS: m/e 286.9 (M+H)⁺

Intermediate 58

5-[5-Bromo-2-(4-fluorophenyl)-1,3-oxazol-4-yl]-2-(methylsulfanyl)pyridine

The target compound was prepared in an analogous manner to Intermediate27 starting with Intermediate 57. LC/MS: m/e 366.8 (M+H)⁺

Intermediate 59

(R)-5-[2-(4-Fluorophenyl)-1,3-oxazol-4-yl]-2-(methylsulfinyl)pyridineand(S)-5-[2-(4-Fluorophenyl)-1,3-oxazol-4-yl]-2-(methylsulfinyl)pyridine

To a solution of Intermediate 54 (1.8 g, 6.3 mmol) in DCM (400 mL) at 0°C. was added a solution of mCPBA (1.4 g, 6.3 mmol) in DCM (100 mL)dropwise over 4 h. Upon complete addition, the solution was stirred foran additional 30 min. Upon completion of the reaction as judged by LC/MSanalysis, the reaction was quenched with sat. NaHSO₃ solution, extractedwith DCM, washed with sat. Na₂CO₃ solution, brine, dried over MgSO₄,filtered, concentrated and purified by on silica gel to afford the titlecompound (1.14 g). LC/MS: m/e 302.9 (M+H)⁺.

Intermediate 60

(R)-5-[5-Bromo-2-(4-fluorophenyl)-1,3-oxazol-4-yl]-2-(methylsulfinyl)pyridineand(S)-5-[5-Bromo-2-(4-fluorophenyl)-1,3-oxazol-4-yl]-2-(methylsulfinyl)pyridine

The target compound was prepared in an analogous manner to Intermediate27 starting with Intermediate 59. LC/MS: m/e 282.8 (M+H)⁺.

Intermediate 61

1H-Pyrazole-4-carboxamide

The mixture of 1H-pyrazole-4-carboxylic acid (2.0 g, 17.8 mmol) andthionyl chloride (20 mL, 168 mmol) was heated to reflux. After 4 h, thereaction mixture was concentrated, and then dried at reduced pressurefor 0.5 h. The resulting residue was dissolved in CH₂Cl₂ (35 mL), cooledto 0° C. and added to a solution of ammonium hydroxide (46.8 mL, 357mmol) in CH₂Cl₂ (20 mL). The reaction mixture was warmed to rt andstirred for 12 h. After which point, the mixture was concentrated andCH₃OH/CH₂Cl₂ (1:10, 40 ml) were added and stirred for 10 min. Thesolution was filtered and washed with CH₃OH/CH₂Cl₂ (1:10). The filtratewas concentrated to give the title compound (1.5 g), which was used inthe next step without purification. LC/MS: m/e 112.0 (M+H)⁺.

Intermediate 62

1-Ethyl-1H-pyrazole-4-carboxamide

To a solution of intermediate 61 (1.5 g, 13.5 mmol) in DMF (4 mL) wasadded powdered K₂CO₃ (5.6 g, 40.5 mmol). After 10 min, bromoethane (1.2mL, 16.2 mmol) was added and the mixture was stirred at rt for 12 h. Thereaction mixture was diluted with EtOAc, washed with water, dried overMgSO₄ and concentrated to afford the title compound as a white solid(1.0 g), which was used in the next step without purification. LC/MS:m/e 140.1 (M+H)⁺.

Intermediate 63

Methyl5-[2-(1-ethyl-1H-pyrazol-4-yl)-1,3-oxazol-4-yl]pyridine-2-carboxylate

To a solution of Intermediate 39 (650 mg, 2.5 mmol) in toluene (20 mL)in a sealed tube was added Intermediate 62 (876 mg, 6.3 mmol). Thereaction mixture was heated to 120° C. for 12 h. The reaction mixturewas then concentrated and purified on silica gel to afford the titlecompound as a white solid (100 mg). LC/MS: m/e 299.2 (M+H)⁺.

Intermediate 64

Methyl5-[5-bromo-2-(1-ethyl-1H-pyrazol-4-yl)-1,3-oxazol-4-yl]pyridine-2-carboxylate

The target compound was prepared in an analogous manner to Intermediate27 starting with Intermediate 63. LC/MS: m/e 379.2 (M+H)⁺.

Intermediate 65

5-(2-Cyclopropyl-1,3-oxazol-4-yl)-2-(methylsulfonyl)pyridine

The target compound was prepared in an analogous manner to Intermediate44 except starting with Intermediate 43. LC/MS: m/e 264.9 (M+H)⁺.

Intermediate 66

5-(5-Bromo-2-cyclopropyl-1,3-oxazol-4-yl-2-(methylsulfonyl)pyridine

The target compound was prepared in an analogues manner to Intermediate27 starting with Intermediate 62. LC/MS: m/e 344.8 (M+H)⁺.

Intermediate 67

Methyl 5-{[(cyclobutylcarbonyl)oxy]acetyl}pyridin-2-carboxylate

The target compound was prepared in an analogous manner to Intermediate40 except that Intermediate 39 was coupled with cyclobutyl carboxylicacid. LC/MS: m/e 278.0 (M+H)⁺

Intermediate 68

Methyl 5-(2-cyclobutyl-1,3-oxazol-4-yl)pyridine-2-carboxylate

The target compound was prepared in an analogous manner to Intermediate44 starting with Intermediate 64. LC/MS: m/e 259.1 (M+H)⁺

Intermediate 69

Methyl 5-(5-bromo-2-cyclobutyl-1,3-oxazol-4-yl)pyridine-2-carboxylate

The target compound was prepared in an analogous manner to Intermediate27 starting with Intermediate 68. LC/MS: m/e 338.9 (M+H)⁺

Intermediate 70

Methyl5-({[(5-chloropyridin-3-yl)carbonyl]oxy}acetyl)pyridine-2-carboxylate

The target compound was prepared in an analogous manner to Intermediate40 except that intermediate 39 was coupled with5-chloropyridine-3-carboxylic acid. LC/MS: m/e 335.0 (M+H)⁺.

Intermediate 71

Methyl5-[2-(5-chloropyridin-3-yl)-1,3-oxazol-4-yl]pyridine-2-carboxylate

The target compound was prepared in an analogous manner to Intermediate44 starting with Intermediate 70. LC/MS: m/e 315.9 (M+H)⁺.

Intermediate 72

Methyl5-[5-bromo-2-(5-chloropyridin-3-yl)-1,3-oxazol-yl]pyridine-2-carboxylate

The target compound was prepared in an analogous manner to Intermediate27 starting with Intermediate 71. LC/MS: m/e 395.8 (M+H)⁺.

Intermediate 73

{5-[2-(4-Fluorophenyl)-1,3-oxazol-4-yl]pyridin-2-yl}acetonitrile

The target compound was prepared in an analogous manner to Intermediate11 except that Intermediate 1 was coupled with(5-bromopyridin-2-yl)acetonitrile. LC/MS: m/e 280.0 (M+H)⁺.

Intermediate 74

{5-[Bromo-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyridin-2-yl}acetonitrile

The target compound was prepared in an analogous manner to Intermediate27. LC/MS: m/e 359.8 (M+H)⁺.

Intermediate 75

1-{5-[2-(4-Fluorophenyl)-1,3-oxazol-4-yl]pyridin-2-yl}-3-hydroxycyclobu-tanecarbonitrile

To a solution of Intermediate 73 (100 mg, 0.4 mmol) in DMF (8 mL) at rtwas added NaH (31.5 mg, 0.8 mmol), followed by epichlorohydrin (39.8 mg,0.4 mmol). The resulting solution was stirred at rt for hl. Uponcompletion of the reaction as judged by TLC analysis, the reaction wasquenched with H₂O, extracted with EtOAc, washed with brine, dried overMgSO₄, filtered, concentrated and purified on silica gel to afford thetitle compound (16 mg). LC/MS: m/e 336.1 (M+H)⁺.

Intermediate 76

1-{5-[5-Bromo-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyridin-2-yl}-3-hydroxycyclobutanecarbonitrile

The target compound was prepared in an analogous manner to Intermediate27. LC/MS: m/e 415.9 (M+H)⁺.

Intermediate 77

2-{5-[2-(4-Fluorobenzyl)-1,3-oxazol-4-yl]pyridin-2-yl}propan-2-ol

The target compound was prepared in an analogous manner to Intermediate11 except that Intermediate 1 was replaced with Intermediate 25. LC/MS:m/e 313.1 (M+H)⁺.

Intermediate 78

2-{5-[5-Bromo-2-(4-fluorobenzyl)-1,3-oxazol-4-yl]pyridin-2-yl}propan-2-ol

The target compound was prepared in an analogous manner to intermediate27. LC/MS: m/e 393.0 (M+H)⁺.

Intermediate 79

Methyl 2-[2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyrimidine-5-carboxylate

The target compound was prepared in an analogous manner to Intermediate11 except that Intermediate 1 was coupled with methyl2-chloropyrimidine-5-carboxylate. LC/MS: m/e 300.1 (M+H)⁺.

Intermediate 80

Methyl2-[5-bromo-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyrimidine-5-carboxylate

The target compound was prepared in an analogous manner to Intermediate27 starting with Intermediate 79. LC/MS: m/e 377.9 (M+H)⁺.

Intermediate 81

6-[2-(4-Fluorophenyl)-1,3-oxazol-4-yl]-3,4-dihydroisoquinolin-1(2H)-one

The target compound was prepared in an analogous manner to Intermediate11 except that Intermediate 1 was coupled with6-bromo-3,4-dihydroisoquinolin-1(2H)-one (Bioorg. Med. Chem. Lett.,2006, 16, 2584). LC/MS: m/e 309.3 (M+H)⁺.

Intermediate 82

6-[5-Bromo-2-(4-fluorophenyl)-1,3-oxazol-4-yl]-3,4-dihydroisoquinolin-1-(2H)-one

The target compound was prepared in an analogous manner to Intermediate27 starting with Intermediate 81. LC/MS: m/e 388.9 (M+H)⁺.

Intermediate 83

7-Bromoquinoline-3-carbaldehyde

The title compound was prepared using the procedure described by Sato,I.; Nakao, T.; Sugie, R.; Kawasaki, T.; Soai, K. Synthesis 2004, 9,1419.

Intermediate 84

7-Bromo-3-(difluoromethyl)quinoline

Dissolved the Intermediate 83 (72 mg, 0.30 mmol) in CH₂Cl₂ (1 mL) andadded a solution of Deoxo-Fluor (0.096 mL, 0.519 mmol) in CH₂Cl₂ (1 ml)followed by EtOH (0.004 mL, 0.069 mmol). Stirred overnight at rt.Diluted with CH₂Cl₂ and added sat'd. NaHCO₃. Extracted with CH₂Cl₂ (3×),dried over MgSO₄, filtered, evaporated and dried under high vac at rt.Light yellow oil. Purified by prep TLC (SiO₂, 20×20 cm, 1000 microns, 1plate; hexane-EtOAc, 9:1) to afford title compound (59 mg). LC/MS:[M+H]⁺ m/e 258, 260 (M+H)⁺.

Intermediate 85

3-(Difluoromethyl)-7-[2-(4-fluorophenyl)-1,3-oxazol-4-yl]quinoline

The target compound was prepared in an analogous manner to Intermediate11 except that Intermediate 1 was coupled with7-Bromo-3-(difluoromethyl)quinoline. LC/MS: m/e 341.5.

Intermediate 86

7-[5-Bromo-2-(4-fluorophenyl)-1,3-oxazol-4-yl]-3-(difluoromethyl)quinoline

The target compound was prepared in an analogous manner to Intermediate27 starting with Intermediate 85 LC/MS: m/e 421 (M+H)⁺.

Intermediate 87

6-Bromo-2-(difluoromethyl)quinoline

Suspended 6-bromoquinoline-2-carbaldehyde (472 mg, 2 mmol) in CH₂Cl₂ (2mL) and added a solution of Deoxo-Fluor (0.627 mL, 3.4 mmol) in CH₂Cl₂(2 mL) followed by EtOH (0.023 mL, 0.4 mmol). Stirred for 48 hrs at rt.Diluted with CH₂Cl₂ and added sat'd. NaHCO₃. Extracted with CH₂Cl₂ (3×),washed extracts with brine (1×), dried over MgSO₄, filtered, evaporatedand dried under high vac at rt. The light brown solids were dissolved ina small amount of CH₂Cl₂-MeOH and stirred with a small amount of silicagel for 15 min. Filtered, evaporated and dried under high vac at rt toafford the title compound (491 mg). LC/MS: m/e 258, 260 (M+H)⁺.

Intermediate 88

2-(Difluoromethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline

Mixed the Intermediate 87 (504 mg, 1.953 mmol), bis(pinacolato)diboron(506 mg, 1.992 mmol), PdCl₂(dppf) (43 mg, 0.059 mmol) and KOAc (575 mg,5.86 mmol) with DMSO (4.0 mL) in a sealed vial. Degassed by bubbling inN₂ gas and then blanketing vessel with N₂ and sealed with Teflonstopper. Heated to 80° C. Heated and stirred overnight.

Cooled to rt after 16 hrs. Diluted with water and extracted with EtOAc(3×), washed with brine (1×), dried over MgSO₄, decolorized withcharcoal, filtered, evaporated and dried under high vac at rt to affordthe title compound (788 mg). LC/MS: m/e 306 (M+H)⁺.

Intermediate 89

2-(Difluoromethyl-6-[2-(4-fluorophenyl)-1,3-oxazol-4-yl]quinoline

Dissolved 2-(4-fluorophenyl)-1,3-oxazol-4-yl trifluoromethanesulfonate(185 mg, 0.593 mmol) and Intermediate 88 (263 mg, 0.652 mmol) in DMF(3.2 mL) and added PdCl₂(dppf) (13 mg, 0.018 mmol) followed by Na₂CO₃(314 mg, 2.97 mmol) and water (0.72 mL) in a sealed tube. The flask wassealed with a Teflon stopper and heated at 90° C. After 5 h the reactionwas cooled to rt, diluted with water and extracted with CH₂Cl₂ (3×).Washed extracts with brine (1×), dried over MgSO₄, decolorized withcharcoal and filtered through filtercel. Evaporated filtrate to drynessand dried under high vac at rt. The brown solids were purified by prepTLC (SiO₂, 20×20 cm, 1000 microns, 3 plates; hexane-EtOAc, 3:1) toafford the title compound (109 mg). LC/MS: m/e 341 (M+H)⁺.

Intermediate 90

6-[5-Bromo-2-(4-fluorophenyl)-1,3-oxazol-4-yl]-2-(difluoromethyl)quinoline

The target compound was prepared in an analogous manner to Intermediate27 starting with Intermediate 89. LC/MS: m/e 421 (M+H)⁺.

Intermediate 91

6-Bromo-N,N-dimethylquinoline-2-carboxamide

Suspended the 6-bromoquinoline-2-carboxylic acid (1.0 g, 3.93 mmol) inCH₂Cl₂ (20 mL), added DMF (0.91 mL, 11.78 mmol) and cooled in an icebath. Added oxalyl chloride (0.688 mL, 7.86 mmol) dropwise over a fewmin. Warmed to rt and stirred for 1 hr then bubbled in dimethylamine gasfor several min. The dark amber mixture was stirred at rt overnight. Inam, the solution was diluted with water and extracted with CH₂Cl₂ (3×).Washed extracts with brine (1×), dried over MgSO₄, decolorized withcharcoal, filtered, evaporated and dried under high vac, rt to affordthe title compound (990 mg). LC/MS: m/e 279, 281 (M+H)⁺.

Intermediate 92

6-[2-(4-Fluorophenyl)-1,3-oxazol-4-yl]-N,N-dimethylquinoline-2-carboxamide

The target compound was prepared in an analogous manner to Intermediate11 except that Intermediate 1 was coupled with Intermediate 91. LC/MS:m/e 362.4 (M+H)⁺.

Intermediate 93

6-[5-Bromo-2-(4-fluorophenyl)-1,3-oxazol-4-yl]-N,N-dimethylquinoline-2-carboxamide

The target compound was prepared in an analogous manner to Intermediate27 starting with Intermediate 92. LC/MS: m/e 442.1 (M+H)⁺.

Intermediate 94

3-Chloro-6-(methylsulfanyl)pyridazine

Dissolved 2,5-dichloropyridazine (8.7 g, 58.4 mmol) in DMF (30 mL) andadded a solution of CH₃SNa (4.1 g, 58.5 mmol) in DMF (60 mL) over 15min. Mild exotherm which was controlled by use of a cold water bath.Stirred at rt for 12 h. Evaporated much of the DMF (˜50 mL) then dilutedwith a large volume of water when solid precipitates. Stirred at rt for2 h then filtered the white solids and washed with water. Dissolved thesolid in CH₂Cl₂, separated out the water and dried over MgSO₄. Filtered,evaporated and dried under high vac at rt to afford the title compound(5.77 g). LC/MS: m/e 161 (M+H)⁺.

Intermediate 95

3-[2-(4-Fluorophenyl)-1,3-oxazol-4-yl]-6-(methylsulfanyl)pyridine

The target compound was prepared in an analogous manner to Intermediate11 except that Intermediate 1 was coupled with Intermediate 94. LC/MS:m/e 288 (M+H)⁺.

Intermediate 96

3-[2-(4-Fluorophenyl)-1,3-oxazol-4-yl]-6-(methylsulfonyl)pyridazine

Intermediate 95 (135 mg, 0.47 mmol) in MeOH (25.0 mL) was treated with asolution of oxone (867 mg, 1.41 mmol) in water (5.0 mL) dropwise andstirred at rt. The solution was then evaporated to dryness, extractedwith CH₂Cl₂ (3×). The combined organic extracts were dried over MgSO₄,filtered and evaporated to afford the title compound (134 mg). LC/MS:m/e 320 (M+H)⁺.

Intermediate 97

3-[5-Bromo-2-(4-fluorophenyl-1,3-oxazol-4-yl]-6-(methylsulfonyl)pyridazine

The target compound was prepared in an analogous manner to Intermediate27 starting with Intermediate 96. LC/MS: m/e 399.7 (M+H)⁺.

Intermediate 98

Ethyl(1S,2S)-2-(4-bromophenyl)cyclopropanecarboxylate

To a 1-neck, 1-L round bottom flask equipped with a magnetic stirrer wasadded 265 mL methyl tert-butyl ether. The flask was evacuated andflushed with nitrogen three times.2,2′-Isopropylidenebis[(4R)-4-tert-butyl-2-oxazolidine] (2.39 g, 8.03mmol) was added, followed by copper(I) tridluoromethanesulfonate benzenecomplex (4.49 g, 8.03 mmol). The green suspension was stirred at roomtemperature for about 2 hours and was then filtered. The filtrate wasadded to a 4-neck, 5-L, round bottom flask equipped with a mechanicalstirrer, thermocouple, nitrogen bubbler, and addition funnel. Then,4-bromostyrene (150 g, 0.803 mol) was added to this solution and thereaction was cooled to 0° C. via an ice/water bath. Ethyl diazoacetate(167 mL, 1.606 mol) was dissolved in 1675 mL of MTBE and the solutionwas evacuated/flushed with nitrogen three times. This solution was thenadded to an addition funnel and added dropwise to the reaction mixture.A slight exotherm was observed. The ethyl diazoacetate was allowed toadd slowly over the weekend and the reaction slowly warmed to roomtemperature. The reaction was poured into a large extractor and dilutedwith 4 L MTBE. The organics were washed with 2×1 L 3% aq. ammoniumhydroxide and 2 L brine, dried over anhydrous magnesium sulfate,filtered, and concentrated. The residue was dissolved in heptane and asmall amount of dichloromethane, injected onto an ISCO 1500 g columnprepacked in heptane. The column was eluted with 100% heptane over 1column volume, 0-20% ethyl acetate/heptane over 6.5 column volumes, andheld at 20% ethyl acetate/heptane over 8 column volumes. The productcontaining fractions were collected and concentrated to give 191 g(yield 88%) of the title compound. 1H NMR (500 MHz, (CDCl₃): 7.42 (d,2H), 7.01 (d, 2H), 4.21 (q, 2H), 2.49 (m, 1H), 1.88 (m, 1H), 1.62 (m,2H), 1.25 (t, 3H).

The compounds in Table 5 were prepared from the appropriate startingmaterials using the procedure for Example 12.

TABLE 5

LCMS: found Example R₂ R₃ m/e (M + H) 57

477.1 58

478.1 59

438.1 60

439.1 61

437.2 62

425.1 63

424.2 64

423.1 65

445.0 66

453.0 67

508.9 68

507.9 69

454.0

Example 70

5-{5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}pyridine-2-carbonitrile

The title compound was prepared in an analogous manner to Example 12starting with Intermediate 33. LC/MS: mile 409.9 (M+H)⁺. ¹H NMR (500MHz, Acetone-d6): δ 7.39 (m, 2H), 7.48 (d, J=8.5 Hz, 1H), 7.83 (m, 1H),8.05 (d, J=8.5 Hz, 1H), 8.24 (m, 2H), 8.45 (d, J=2.5 Hz, 1H), 8.72 (m,1H), 9.44 (d, J=1.5 Hz, 1H).

Example 71

5-Chloro-2-({2-(4-fluorophenyl)-4-[6-(1,2,4-oxadiazol-3-yl)pyridin-3-yl]-1,3-oxazol-5-yl}sulfanyl)pyridine

To Example 70 (100 mg, 0.25 mmol) in 10 mL EtOH was added 1.0 mL of 50wt % aqueous NH₂OH and 15 mg of K₂CO₃. The reaction was heated to 120°C. for 5 min via microwave irradiation. The reaction mixture wasconcentrated to dryness and the residue was dissolved in 5 mLtriethylorthoformate, 10 mL EtOH and 1 mL of TFA. The reaction washeated to 100° C. for 10 min via microwave irradiation. The volatileswere removed and the residue was purified on silica gel to afford thetitle compound (64 mg). LC/MS: m/e 452.0 (M+H)⁺. ¹H NMR (500 MHz,Acetone-d6): δ 7.37-7.41 (m, 3H), 7.82 (m, 1H), 8.27 (m, 2H), 8.47 (d,J=2.0 Hz, 1H), 8.69 (d, J=6.5 Hz, 1H), 9.47 (s, 1H).

Example 72

5-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}pyrimidine-2-carbonitrile

The title compound was prepared in an analogous manner to Example 12starting with Intermediate 31. LC/MS: m/e 410.0 (M+H)⁺. ¹H NMR (500 MHz,Acetone-d6): δ 7.41 (m, 2H), 7.53 (d, J=8.5 Hz, 1H), 7.84 (m, 1H), 8.26(m, 2H), 8.45 (d, J=2.5 Hz, 1H), 9.61 (s, 2H).

Example 73

1-(5-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}pyrimidin-2-yl)ethanone

A solution of5-{5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}pyrimidine-2-carbonitrile(Example 72) (87 mg, 0.21 mmol) in THF (5 mL) was treated withmethylmagnesium bromide (0.7 mL, 2.1 mmol, 3.0 M in THF) at rt. Uponcompletion of the reaction as judged by TLC analysis, the solution wasdiluted with saturated aq NH₄Cl solution and extracted with EtOAc. Theorganic layer was removed, dried over MgSO₄, filtered and concentratedgiving rise to an oil. The oil was purified on silica gel to afford thetitle compound (13 mg). LC/MS: m/e 427.0 (M+H)⁺. ¹H NMR (500 MHz,Acetone-d6): δ 2.70 (s, 3H), 7.41 (m, 2H), 7.51 (d, J=9.0 Hz, 1H), 7.83(m, 1H), 8.27 (m, 2H), 8.45 (d, J=2.5 Hz, 1H), 9.57 (s, 2H).

Example 74

2-(5-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}pyrimidin-2-yl)propan-2-ol

A solution of1-(5-{5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}pyrimidin-2-yl)ethanone(Example 73) (12 mg, 0.03 mmol) in THF (5 mL) was treated withmethylmagnesium bromide (0.09 mL, 0.3 mmol, 3.0 M in THF) at it. Uponcompletion of the reaction as judged by TLC analysis, the solution wasdiluted with saturated aq NH₄Cl solution and extracted with EtOAc. Theorganic layer was removed, dried over MgSO₄, filtered and concentratedgiving rise to an oil. The oil was purified on silica gel to afford thetitle compound (6.3 mg). LC/MS: m/e 443.0 (M+H)⁺. ¹H NMR (500 MHz,Acetone-d6): δ 1.54 (s, 6H), 4.56 (s, 1H), 7.39 (m, 2H), 7.47 (d, J=8.5Hz, 1H), 7.82 (m, 1H), 8.25 (m, 2H), 8.45 (d, J=2.5 Hz, 1H), 9.39 (s,2H).

The compounds in Table 6 were prepared from the appropriate startingmaterials using the procedure for Example 12.

TABLE 6

LCMS: found Example R₂ R₃ m/e (M + H) 75

427.0 76

438.0 77

443.9

Example 78

5-Chloro-2-({2-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-1,3-oxazol-5-yl}sulfanyl)pyridine

A stirred solution of Intermediate 29 (1.30 g, 3.30 mmol),5-chloropyridine-2-thiol (573 mg, 3.90 mmol), and K₂CO₃ (1.36 g, 9.80mmol) dissolved in 60 mL of NMP was heated to 60° C. for 1 h. Afterwhich point, the solution was diluted with dist. H₂O and EtOAc. Theorganic layer was removed followed by drying over MgSO₄, filtration andconcentration giving rise to an oil. The oil was purified on silica gelto afford the title compound (130 mg). LC/MS: m/e 460.7 (M+H)⁺. ¹H NMR(500 MHz, CDCl₃): δ 3.09 (s, 3H), 7.05 (d, J=8.5 Hz, 1H), 7.22 (m, 2H),7.56 (m, 1H), 8.01 (d, J=8.5 Hz, 2H), 8.19 (m, 2H), 8.37 (d, J=8.5 Hz,2H), 8.41 (d, J=2.5 Hz, 1H).

Example 79

Methyl-4-{5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}benzoate

A stirred solution of Intermediate 27 (500 mg, 1.30 mmol),5-chloropyridine-2-thiol (290 mg, 2.00 mmol), and K₂CO₃ (551 mg, 4.00mmol) dissolved in 20 mL of NMP was heated to 80° C. for 12 h. Afterwhich point, the solution was diluted with dist. H₂O and EtOAc. Theorganic layer was removed followed by drying over MgSO₄, filtration andconcentration giving rise to an oil. The oil was purified on silica gelto afford the title compound (330 mg). LC/MS: m/e 440.9 (M+H)⁺. ¹H NMR(500 MHz, CDCl₃): δ 3.95 (s, 3H), 7.02 (d, J=8.5 Hz, 1H), 7.22 (m, 2H),7.56 (m, 1H), 8.11 (d, J=8.5 Hz, 2H), 8.13 (m, 2H), 8.25 (d, J=8.5 Hz,2H), 8.43 (d, J=2.5 Hz, 1H).

Example 80

2-(4-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}phenyl)propan-2-ol

A solution ofmethyl-4-{5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}benzoate(Example 79) (127 mg, 0.29 mmol) in THF (10 mL) was treated withmethylmagnesium bromide (0.50 mL, 1.4 mmol, 3.0 M in THF) at rt. Uponcompletion of the reaction as judged by TLC analysis, the solution wasdiluted with saturated aq NH₄Cl solution and extracted with EtOAc. Theorganic layer was removed, dried over MgSO₄, filtered and concentratedgiving rise to an oil. The oil was purified on silica gel to afford thetitle compound (100 mg). LC/MS: m/e 441.0 (M+H)⁺.

Example 81

4-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}-1-(methylsulfonyl)piperidiniumtrifluoroacetate

A solution of Intermediate 35 (100 mg, 0.925 mmol) in CH₂Cl₂ (10 mL) wasstirred at rt for 16 h. Upon completion of the reaction as judge by TLC,the solution was diluted with CH₂Cl₂ (20 mL) and sat aq. Na₂S₂O₃ (30mL). The organic layer was removed, dried over MgSO₄, filtered andconcentrated to afford the corresponding bromide. The material was takenonto the next step directly. At this point, a solution of5-chloropyridine-2-thiol (79 mg, 0.564 mmol) in DME (2 mL) was addedK₂CO₃ (113 mg, 0.818 mmol) and stirred at rt for 15 min. A solution ofthe freshly prepared bromide (110 mg, 0.273 mmol), neocuproine (14.0 mg,0.068 mmol) and CuI (13 mg, 0.068 mmol) in DME (2 mL) was added to themixture and heated to 90° C. for 2 h. The solution was allowed to coolto rt, concentrated under vacuum and the residue was purified by reversephase HPLC to afford 9 mg of the final compound as a TFA salt. LCMS: m/z468.0 (M+H)⁺.

The compounds in Table 7 were prepared from the appropriate startingmaterials using the procedure for Example 12.

TABLE 7

LCMS: found Example R₁ R₃ m/e (M + H) 82

442.1 83

442.1

Example 84

Methyl2-(5-{5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}pyridin-2-yl)-2-methylpropanoate

The title compound was prepared in an analogous manner to Example 12starting with Intermediate 37. LC/MS: m/e 484.1 (M+H)⁺.

Example 85

3-(5-{5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}pyridin-2-yl)-2,3-dimethylbutan-2-ol

The title compound was prepared in an analogous manner to Example 80starting with Example 84. LC/MS: m/e 484.2 (M+H)⁺. ¹H NMR (500 MHz,acetone-d6): δ 1.04 (s, 6H), 1.41 (s, 6H), 7.39 (m, 3H), (7.36 (d, J=8Hz, 1H), 7.80 (dd, J=2.5, 8.5 Hz, 1H), 8.24 (m, 2H), 8.44 (m, 2H), 9.23(d, J=1.5 Hz, 1H).

Example 86

2-(5-{5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}pyridin-2-yl)-2-methylpropan-1-ol

To a solution of Example 84 (120 mg, 0.2 mmol) in THF (10 mL) at −78° C.was added DIBAl-H (1.0M/toluene, 0.6 mL, 0.6 mmol). The resultingsolution was stirred at −78° C. for 1 h. The reaction mixture was thenpoured into a vigorously stirred Rochelle salt solution/EtOAc (1:1).Upon clarification of the organic layer, the layers were separated,dried over MgSO₄, filtered, concentrated and purified on silica gel toafford the title compound (95.7 mg). LC/MS: m/e 456.1 (M+H)⁺. ¹H NMR(500 MHz, acetone-d6): δ 1.35 (s, 6H), 3.73 (d, J=5.5 Hz, 2H), 4.08 (t,J=5.5 Hz, 1H) 7.40 (m, 3H), 7.58 (d, J=7.5 Hz, 1H), 7.82 (dd, J=3, 9 Hz,1H), 8.25 (m, 2H), 8.39 (dd, J=2.5, 8.5 Hz, 1H), 8.47 (d, 2.5J=2.5 Hz,1H), 9.21 (s, 1H).

Example 87

Methyl5-{5-[(5-chloropyridin-2-yl)sulfanyl]-2-cyclopropyl-1,3-oxazol-4-yl}pyridine-2-carboxylate

To a solution of Intermediate 45 (2.2 g, 6.8 mmol) in NMP (65 mL) at rtwas added 5-chloropyridine-2-thiol (1.19 g, 8.17 mmol) and K₂CO₃ (2.82g, 20.4 mmol). The resulting solution was heated at 60° C. overnight.Upon completion of the reaction as judged by LC/MS analysis, thereaction was dilute with water, extract with EtOAc, the combined organiclayers was washed with brine, dried over MgSO₄, filtered, concentratedand purified on silica gel to afford the title compound (2.54 g). LC/MS:m/e 387.9 (M+H)⁺.

Example 88

1-(5-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-cyclopropyl-1,3-oxazol-4-yl}pyridin-2-yl)ethanone

To a solution of Intermediate 87 (2.54 g, 6.55 mmol) in THF (260 mL) atrt was added MeMgBr (3.0M/Et₂O, 21.8 mL, 65.5 mmol), the resultingmixture was stirred at rt for 2 h. Upon completion of the reaction asjudged by TLC analysis, the reaction was quenched by addition ofsat.NH₄Cl solution, extracted with EtOAc, the organic layer was washedwith brine, dried over MgSO₄, filtered, concentrated and purified onsilica gel to afford the title compound (188 mg). LC/MS: m/e 371.8(M+H)⁺.

Example 89

1-(5-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-cyclopropyl-1,3-oxazol-4-yl}pyridin-2-yl)ethanol

To a solution of Example 88 (16 mg, 0.04 mmol) in MeOH (10 mL) at rt wasadded NaBH₄ (1.6 mg, 0.04 mmol). The resulting solution was stirred atrt for 1 h. Upon completion of the reaction as judged by TLC analysis,the reaction was concentrated to dryness and purified on silica gel toafford the titled compound (12 mg). LC/MS: m/e 373.9 (M+H)⁺.

Example 90

2-(5-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-cyclopropyl-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol

To a solution of Example 87 (2.54 g, 6.5 mmol) in THF (260 mL) at rt wasadded MeMgBr (3.0M/Et₂O, 21.8 mL, 65.5 mmol). The resulting mixture wasstirred at rt for 2 h. Upon completion of the reaction as judged by TLCanalysis, the reaction was quenched by addition of sat.NH₄Cl solutionand extracted with EtOAc. The organic layer was washed with brine, driedover MgSO₄, filtered, concentrated and purified on silica gel to affordthe title compound (1.77 g). LC/MS: m/e 387.9 (M+H)⁺. ¹H NMR (500 MHz,CDCl₃): δ 1.22 (m, 4H), 1.56 (s, 6H), 2.19 (m, 1H), 4.85 (s, 1H), 6.96(d, J=8.5 Hz, 1H), 7.42 (d, J=8 Hz, 1H), 7.55 (dd, J=2.5, 8.5 Hz, 1H),8.32 (dd, J=2, 8.5 Hz, 1H), 8.43 (d, J=2.5 Hz, 1H), 9.14 (d, J=1.5 Hz,1H).

The compounds in Table 8 were prepared from the appropriate startingmaterials using the procedure for Example 12.

TABLE 8

LCMS: found Example R₁ R₃ m/e (M + H) 91

383.1 92

388.3 93

405.1 94

405.1 95

389.0

Example 96

2-(6-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}pyridazin-3-yl)propan-2-ol

The target compound was prepared in an analogous manner to Example 12except that Intermediate 12 was replaced with Intermediate 47. LC/MS:m/e 443.2 (M+H)⁺. ¹H NMR (500 MHz, Acetone-d6): δ 1.64 (s, 6H), 4.70 (s,1H), 7.38 (t, J=8.5 Hz, 2H), 7.43 (d, J=8.5 Hz, 1H), 7.76 (dd, J=2.5,8.5 Hz, 1H), 8.09 (d, J=9 Hz, 1H), 8.22 (m, 2H), 8.27 (d, J=8.5 Hz, 1H),8.43 (d, J=2.5 Hz, 1H).

Example 97

Ethyl5-{5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}isoxazole-3-carboxylate

The target compound was prepared in an analogous manner to Example 78except that Intermediate 29 was replaced with Intermediate 52. LC/MS:m/e 445.9 (M+H)⁺

Example 98

2-(5-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}isoxazol-3-yl)propan-2-ol

The title compound was prepared in an analogous manner to Example 80starting with Example 97. LC/MS: m/e 431.9 (M+H)⁺

Example 99

Methyl2-{5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}-1,3-thiazole-4-carboxylate

The target compound was prepared in an analogous manner to Example 78except that Intermediate 29 was replaced with Intermediate 54. LC/MS:m/e 447.9 (M+H)⁺

Example 100

2-(2-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}-1,3-thiazol-4-yl)propan-2-ol

The title compound was prepared in an analogous manner to Example 80starting with Example 99. LC/MS: m/e 447.9 (M+H)⁺.

Example 101

5-Chloro-2-({2-cyclopropyl-4-[6-(methylsulfonyl)pyridin-3-yl]-1,3-oxazo1-5-yl}sulfanyl)pyridine

The target compound was prepared in an analogous manner to Example 78except that Intermediate 29 was replaced with Intermediate 66. LC/MS:m/e 407.8 (M+H)⁺. ¹H NMR (500 MHz, CDCl₃): δ 1.22 (m, 4H), 2.20 (m, 1H),3.25 (s, 3H), 7.04 (d, J=8.5 Hz, 1H), 7.59 (dd, J=2.5, 8.5 Hz, 1H), 8.12(d, J=8 Hz, 1H), 8.46 (d, J=2 Hz, 1H), 8.59 (dd, J=2, 8.5 Hz, 1H), 9.38(s, 1H).

Example 102

5-Chloro-2-({2-(4-fluorophenyl)-4-[6-(methylsulfonyl)pyridin-3-yl]-1,3-oxazol-5-yl}sulfanyl)pyridine

The target compound was prepared in an analogous manner to Example 78except that Intermediate 29 was replaced with Intermediate 56. LC/MS:m/e 461.8 (M+H)⁺ NMR (500 MHz, CDCl₃): δ 3.28 (s, 3H), 7.14 (d, J=2.5Hz, 1H), 7.24 (t, J=8.5 Hz, 2H), 7.60 (dd, J=2.5, 8.5 Hz, 1H), 8.18 (m,3H), 8.40 (d, J=2.5 Hz, 1H), 8.72 (dd, J=2, 8 Hz, H), 9.49 (d, J=2 Hz,1H).

The compounds in Table 9 were prepared from the appropriate startingmaterials using the procedure for Example 78.

TABLE 9

LCMS: found Example R₁ R₂ m/e (M + H) 103

462.7 104

461.7 105

429.8 106 A and 106B

445.8Note: Example 106 is racemic

Example 107

5-Chloro-2-({2-(4-fluorophenyl)-4-[6-(methylsulfonyl)pyridin-3-yl]-1,3-oxazol-5-yl}sulfanyl)pyrimidine

The target compound was prepared in an analogous manner to Example 78except that Intermediate 56 was coupled with 5-chloropyrimidine-2-thiol.LC/MS: m/e 461.8 (M+H)⁺ NMR (500 MHz, CDCl₃): δ 3.28 (s, 3H), 7.14 (d,J=2.5 Hz, 1H), 7.24 (t, J=8.5 Hz, 2H), 7.60 (dd, J=2.5, 8.5 Hz, 1H),8.18 (m, 3H), 8.40 (d, J=2.5 Hz, 1H), 8.72 (dd, J=2, 8 Hz, 1H), 9.49 (d,J=2 Hz, 1H).

Example 108

(R)-5-Chloro-2-({2-(4-fluorophenyl)-4-[6-(methylsulfinyl)pyridin-3-yl]-1,3-oxazol-5-yl}sulfanyl)pyridineand(S)-5-Chloro-2-({2-(4-fluorophenyl)-4-[6-methylsulfinyl)pyridin-3-yl]-1,3-oxazol-5-yl}sulfanyl)pyridine

The target compound was prepared in an analogous manner to Example 78except that Intermediate 29 was replaced with Intermediate 60. LC/MS:m/e 445.8 (M+11)⁺

Example 109

(R)-5-Fluoro-2-({2-(4-fluorophenyl)-4-[6-(methylsulfinyl)pyridin-3-yl]-1,3-oxazol-5-yl}sulfanyl)pyridineand(S)-5-Fluoro-2-({2-(4-fluorophenyl)-4-[6-(methylsulfinyl)pyridin-3-yl]-1,3-oxazol-5-yl}sulfanyl)pyridine

The target compound was prepared in an analogous manner to Example 108starting with Intermediate 60 and replacing 5-chloropyridine-2-thiolwith 5-fluoropyridine-2-thiol. LC/MS: m/e 445.8 (M+H)⁺

Example 110

Methyl5-(5-[(4-chlorophenyl)sulfanyl]-2-(1-ethyl-1H-pyrazol-4-yl)-1,3-oxazol-4-yl)pyridine-2-carboxylate

The title compound was prepared in an analogous manner to Example 12starting with Intermediate 61. LC/MS: m/e 441.2 (M+H)⁺.

Example 111

2-(5-{5-[(4-chlorophenyl)sulfanyl]-2-(1-ethyl-1H-pyrazol-4-yl)-1,3-oxazol-4-yl)pyridin-2-yl}propan-2-ol

The title compound was prepared in an analogous manner to Example 80starting with Example 110. LC/MS: m/e 441.3 (M+H)⁺.

Example 112

Methyl5-{5-[(5-chloropyridin-2-yl)sulfanyl]-2-(1-ethyl-1H-pyrazol-4-yl)-1,3-oxazol-4-yl)pyridin-2-carboxylate

The title compound was prepared in an analogous manner to Example 12starting with Intermediate 64 and 4-Chlorobenzenethiol was replaced with5-chloropyridine-2-thiol. LC/MS: m/e 441.9 (M+H)⁺.

Example 113

2-(5-{5-[(5-chloropyridin-2-yl)sulfanyl]-2-(1-ethyl-1H-pyrazol-4-yl)-1,3-oxazol-4-ylpyridin-2-yl}propan-2-ol

The title compound was prepared in an analogous manner to Example 80starting with Example 112. LC/MS: m/e 442.1 (M+H)⁺.

Example 114

5-Chloro-2-({2-(4-fluorophenyl)-4-[6-(methylsulfanyl)pyridin-3-yl]-1,3-oxazol-5-yl}sulfanyl)pyridine

The target compound was prepared in an analogues manner to Example 78except that Intermediate 29 was replaced with Intermediate 58. LC/MS:m/e 429.8 (M+H)⁺. NMR (500 MHz, CDCl₃): δ 2.62 (s, 3H), 7.02 (d, J=8.5Hz, 1H), 7.22 (t, J=8.5 Hz, 2H), 7.26 (d, J=8.5 Hz, 1H), 7.55 (dd,J=2.5, 8.5 Hz, 1H), 8.17 (m, 2H), 8.24 (dd, J=2.5, 8.5 Hz, 1H), 8.42 (d,J=2.5 Hz, 1H), 9.20 (s, 1H).

Example 115

Methyl5-{5-[(5-chloropyridin-2-yl)sulfanyl]-2-cyclobutyl-1,3-oxazol-4-yl}pyridine-2-carboxylate

The target compound was prepared in an analogous manner to Example 87except that Intermediate 45 replaced Intermediate 69. LC/MS: m/e 401.9(M+H)⁺

Example 116A and Example 116B

2-(5-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-cyclobutyl-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol

1-(5-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-cyclobutyl-1,3-oxazol-4-yl}pyridin-2-yl)ethanone

To a solution of Example 115 (264 mg, 0.6 mmol) in THF (20 ml) at rt wasadded MeMgBr (3.0M/Et₂O, 2.19 mL, 6.6 mmol) and the resulting mixturewas stirred at rt for 2 h. Upon completion of the reaction as judged byTLC analysis, the reaction was quenched by addition of sat.NH₄Clsolution, extracted with EtOAc, the organic layer was washed with brine,dried over MgSO₄, filtered, concentrated and purified on silica gel toafford the title compound (201 mg) along with methyl ketone as abyproduct.

For 116A: LC/MS: m/e 401.9 (M+H)⁺. ¹H NMR (500 MHz, CDCl₃): δ 1.57 (s,6H), 2.12 (m, 2H), 2.51 (m, 4H), 3.76 (m, 1H), 4.88 (s, 1H), 6.97 (d,J=8.5 Hz, 1H), 7.43 (d, J=8.5 Hz, 1H), 7.56 (dd, J=3.0, 8.5 Hz, 1H),8.34 (dd, J=2.5, 8.5 Hz, 1H), 8.42 (d, J=2.5 Hz, 1H), 9.16 (d, J=1.5 Hz,1H).

For 116B: m/e 385.9 (M+H)⁺. ¹H NMR (500 MHz, CDCl₃): δ 2.10 (m, 2H),2.51 (m, 4H), 2.74 (s, 3H), 3.77 (m, 1H), 4.90 (s, 1H), 7.02 (d, J=8.5Hz, 1H), 7.56 (d, J=7.0 Hz, 1H), 8.10 (d, J=8.5 Hz, 1H), 8.41 (s, 1H),8.50 (d, J=8.0 Hz, 1H), 9.32 (s, 1H).

Example 117

(R)-1-(5-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-cyclobutyl-1,3-oxazol-4-yl}pyridin-2-yl)ethanoland(S)-1-(5-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-cyclobutyl-1,3-oxazol-4-yl}pyridin-2-yl)ethanol

The target compound was prepared in an analogous manner to Example 89except that Example 88 was replaced with Example 116B. LC/MS: m/e 387.9(M+H)⁺. ¹H NMR (500 MHz, CDCl₃): δ 1.52 (d, J=6.5 Hz, 3H), 2.08 (m, 2H),2.50 (m, 4H), 3.75 (m, 1H), 4.13 (br, 1H), 4.93 (m, 1H), 6.95 (d, J=9Hz, 1H), 7.33 (d, J=8 Hz, 1H), 7.54 (dd, J=2.5, 8.5 Hz, 1H), 8.33 (dd,J=2.0, 8.0 Hz, 1 Hz), 8.40 (d, J=2 Hz, 1H), 8.18 (d, J=1.5 Hz, 1H).

Example 118

Methyl5-{2-(5-chloropyridin-3-yl)-5-[(5-chloropyridin-2-yl)sulfanyl]-1,3-oxazol-4-yl}pyridine-2-carboxylate

The target compound was prepared in an analogous manner to Example 78except that Intermediate 29 was replaced with Intermediate 72. LC/MS:mile 458.8 (M+H)⁺.

Example 119

2-(5-{2-(5-Chloropyridin-3-yl)-5-[(5-chloropyridin-2-yl)sulfanyl]-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol

The title compound was prepared in an analogous manner to Example 80starting with Example 118. LC/MS: m/e 458.8 (M+H)⁺. ¹H NMR (500 MHz,CDCl₃): δ 1.60 (s, 6H), 4.81 (s, 1H), 7.13 (d, J=8.5 Hz, 1H), 7.49 (d,J=8.0 Hz, 1H), 7.60 (dd, J=2.5, 8.5 Hz, 1H), 8.44 (m, 3H), 8.74 (d,J=2.5 Hz, 1H), 9.27 (dd, J=2.0, 6.5 Hz, 2H).

Example 120

1-(5-{2-(5-Chloropyridin-3-yl)-5-[(5-chloropyridin-2-yl)sulfanyl]-1,3-oxazol-4-yl}pyridin-2-yl)ethanone

The target compound was prepared in an analogous manner to Example 116 Bstarting with Example 118. LC/MS: m/e 442.8 (M+H)⁺. ¹H NMR (500 MHz,CDCl₃): δ 2.77 (s, 3H), 7.17 (d, J=8.0 Hz, 1H), 7.61 (d, J=7.5 Hz, 1H),8.14 (d, J=7.5 Hz, 1H), 8.39 (s, 1H), 8.44 (s, 1H), 8.58 (d, J=7.5 Hz,1H), 8.75 (s, 1H), 9.28 (s, 1H), 9.45 (s, 1H).

Example 121

(5-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}pyridin-2-yl)acetonitrile

The target compound was prepared in an analogous manner to Example 78except that Intermediate 29 was replaced with Intermediate 74. LC/MS:m/e 422.8 (M+H)⁺. ¹H NMR (500 MHz, CDCl₃): δ 4.00 (s, 3H), 7.08 (d,J=9.0 Hz, 1H), 7.23 (t, J=8.5 Hz, 2H), 7.53 (d, J=8.5 Hz, 1H), 7.57 (dd,J=2.5, 8.0 Hz, 1H), 8.19 (m, 2H), 8.41 (d, J=2.5 Hz, 1H), 8.49 (dd,J=2.0, 8.0 Hz, 1H), 9.33 (d, J=2.5 Hz 1H).

Example 122

1-(5-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}pyridin-2-yl-3-hydroxycyclobutanecarbonitrile

The target compound was prepared in an analogous manner to Example 78except that Intermediate 29 was replaced with Intermediate 76. LC/MS:m/e 478.9 (M+H)⁺. ¹H NMR (500 MHz, Acetone-d6): δ 1.68 (m, 1H), 2.01 (m,1H), 2.33 (m, 1H), 3.73 (m, 1H), 4.03 (m, 1H), 7.40 (m, 3H), 7.80 (m,2H), 8.24 (m, 2H), 8.46 (d, J=2.5 Hz, 1H), 8.52 (dd, J=2.5, 8.5 Hz, 1H),9.18 (s, 1H).

Example 123

2-(5-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-(4-fluorobenzyl)-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol

The target compound was prepared in an analogous manner to Example 78except that Intermediate 29 was replaced with Intermediate 78. LC/MS:m/e 456.0 (M+H)⁺. ¹H NMR (500 MHz, Acetone-d6): δ 1.51 (m, 1H), 4.31 (s,2H), 4.59 (s, 1H), 7.15 (t, J=8.5 Hz, 2H), 7.23 (d, J=8.5 Hz, 1H), 7.47(m, 2H), 7.50 (d, J=8.5 Hz, 1H), 7.79 (dd, J=2.5, 8.5 Hz, 1H), 8.33 (dd,J=2.5, 8.5 Hz, 1H), 8.44 (d, J=2.5 Hz, 1H), 9.10 (d, J=2.0 Hz, 1H).

Example 124

Methyl2-{5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenol)-1,3-oxazol-4-yl}pyrimidine-5-carboxylate

The target compound was prepared in an analogous manner to Example 78except that Intermediate 29 was replaced with Intermediate 80. LC/MS:m/e 442.9 (M+H)⁺. ¹H NMR (500 MHz, CDCl₃): δ 4.02 (s, 3H), 7.20 (t,J=8.5 Hz, 2H), 7.27 (m, 1H), 7.60 (dd, J=2.5, 8.5 Hz, 1H), 8.19 (m, 2H),8.44 (d, J=2.5 Hz, 1H), 9.39 (s, 2H).

The Examples in Table 10 were prepared following the proceduresdescribed in Example 50, Step F.

TABLE 10

LCMS: found Example R₃ m/e (M + H) 125

409.2 126

442.1 127

442.1 128

421.2 129

426.1 130

426.1 131

426.1 132

420.2

Example 133

6-{5-[(4-Chlorophenyl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}-3,4-dihydroisoquinolin-1(2H)-one

The title compound was prepared in an analogous manner to Example 12starting with Intermediate 82. LC/MS: m/e 451.2 (M+H)⁺.

Example 134

7-{5-[(4-Chlorophenyl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}-3-(difluoromethyl)quinoline

Intermediate 86 was dissolved 4-chlorothiophenol (23 mg, 0.157 mmol) inNMP (1 mL) and added a 60% oil dispersion of NaH (6.3 mg, 0.157 mmol).Vigorous gas evolution and reaction mixture became dark purple in color.Stirred at rt for 20 min. then combined a solution of intermediate (36mg, 0.071 mmol) in NMP (1 mL), the above prepared thiolate solution andCuI (13.6 mg, 0.071 mmol) in a sealed vial, degassed with N₂, sealedwith a Teflon stopper and heated to 120° C. Heated for 7 h then cooledto rt and stirred overnight. Diluted with sat'd. NaHCO₃ (9 mL) and coneNH₃ (1 mL) and extracted with EtOAc (3×). Washed extracts with brine(1×), dried over MgSO₄, filtered, evaporated and dried under high vac.at rt. The amber oil was purified by prep TLC (SiO₂, 20×20 cm, 1000microns, 3 plates; hexane-EtOAc, 3:1) to afford the title compound (26mg). LC/MS: m/e 482.9 (M+H)⁺. ¹H NMR (500 MHz, CDCl₃) δ 6.94 (t, J=55.85Hz, 1H), 7.24 (t, J=8.55 Hz, 2H), 7.3 (m, 4H), 8.01 (d, J=8.5 Hz, 1H),8.22 (m, 2H), 8.36 (s, 1H), 8.52 (d, J=8.5 Hz, 1H), 9.06 (s, 1H), 9.1(s, 1H).

Example 135

6-{5-[(4-Chlorophenyl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}-2-(difluoromethyl)quinoline

The title compound was prepared in an analogous manner to Example 12starting with Intermediate 90. LC/MS: m/e 483.1 (M+H)⁺. ¹H NMR (500 MHz,CDCl₃) δ 6.84 (t, J=55.35, 1H), 7.25 (t, J=8.6 Hz, 2H), 7.3 (m, 4H), 7.8(d, J=8.5 Hz, 1H), 8.22 (m, 3H), 8.42 (d, J=8.7 Hz, 1H), 8.69 (dd,J=1.8, 8.9 Hz, 1H), 8.72 (s, 1H).

Example 136

6-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}-N,N-dimethylquinoline-2-carboxamide

The target compound was prepared in an analogous manner to Example 12starting with Intermediate 93. LC/MS: m/e 505.1 (M+H)⁺. ¹H NMR (500 MHz,CDCl3) δ 3.21 (s, 3H), 3.24 (s, 3H), 7.085 (d, J=8.7 Hz, 1H), 7.25 (t,J=8.2 Hz, 2H), 7.56 (d, J=9.1 Hz, 1H), 7.77 (d, J=8.3 Hz, 1H), 8.19 (d,J=8.4 Hz, 1H), 8.24 (m, 2H), 8.35 (d, J=8.8 Hz, 1H), 8.45 (s, 1H), 8.6(d, J=9.2 Hz, 1H), 8.69 (s, 1H).

Example 137

3-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}-6-(methylsulfonyl)pyridazine

The target compound was prepared in an analogous manner to the Example12 starting with Intermediate 97. LC/MS: m/e 462.8 (M+H)⁺. ¹H NMR (500MHz, CDCl₃) δ 3.50 (s, 3H), 7.23 (m, 2H), 7.33 (d, J=8.7 Hz, 1H), 7.63(dd, J=2.1, 8.5 Hz, 1H), 8.15 (m, 2H), 8.3 (d, J=8.8 Hz, 1H), 8.42 (s,1H), 8.58 (t, J=8.7 Hz, 1H).

Example 138

(1S,2S)-2-(4-{5-[(5-chloropyridin-2-yl)thio]-2-cyclopropyl-1,3-oxazol-4-yl}phenyl-N,N-dimethylcyclopropanecarbozamideStep A

A solution of Intermediate 24 (478 mg, 1.858 mmol), PdCl₂ (dppf)-CH₂Cl₂Adduct (68 mg, 0.093 mmol), dppf (51 mg, 0.093 mmol), KOAc (oven dried)(547 mg, 5.57 mmol), bis(pinacolato)diboron (613 mg, 2.415 mmol) indioxane (4.3 mL) was placed under an atmosphere of nitrogen and heatedat 150° C. for 20 min via microwave irradiation. To this mixture wasadded Intermediate 98 (500 mg, 1.858 mmol),bis(triphenylphosphine)palladium (II) chloride (130 mg, 0.186 mmol),sodium carbonate (1 mL of 1 M aqueous solution). The mixture was heatedat 150° C. for 45 min via microwave irradiation. Water was added and themixture was extracted with ethyl acetate. The organics were dried(MgSO₄) and concentrated. The residue was subject to silica column(0-30% EtOAc in hexanes) to afford ethyl(1S,2S)-2-[4-(2-cyclopropyl-1,3-oxazol-4-yl)phenyl]cyclopropanecarboxylate(239 mg, 43%). LC/MS: m/z 298.1 (M+H)⁺.

Step B

A solution of the product from the previous step (400 mg, 1.345 mmol)and NBS (311 mg, 1.749 mmol) in CH₂Cl₂ (4.5 mL) was stirred at rt for 3h. Upon completion of the reaction, the solution was diluted with sat aqNaS₂O₃ solution. The organic layer was removed, dried over MgSO₄,filtered and concentrated giving rise to an oil. The oil was purified onsilica gel to afford the ethyl(1S,2S)-2-[4-(5-bromo-2-cyclopropyl-1,3-oxazol-4-yl)phenyl]cyclopropanecarboxylate(335 mg, 66%). LC/MS: m/z 376.2 (M+H)+.

Step C

A solution of 5-chloropyridine-2-thiol (201 mg, 1.382 mmol) dissolved in2 mL of NMP was treated with NaH (55 mg, 1.382 mmol). The resultingsolution was stirred for 30 min at rt before the product from theprevious step (260 mg, 0.691 mmol) and CuI (132 mg, 0.691 mmol) wereadded. The resulting dark solution was heated to 120° C. for 16 h. Afterwhich point, the solution was poured into a rapidly stirred solution of9:1 NH₄Cl:NH₄OH and EtOAc. Upon clarification of the organic layer,removal of the organic layer was followed by drying over MgSO₄,filtration and concentration giving rise to an oil. The oil was purifiedon silica gel to afford ethyl(1S,2S)-2-(4-{5-[(5-chloropyridin-2-yl)thio]-2-cyclopropyl-1,3-oxazol-4-yl}phenyl)cyclopropanecarboxylate.LC/MS: m/z 441.1 (M+H)+.

Step D

The product from the previous step (140 mg, 0.318 mmol) was dissolved in1 mL of acetonitrile, to which was added 1 mL of water, followed byexcess KOH pellets. The reaction was stirred at 80° C. for 3 h. After itwas cooled to rt, the pH of the reaction mixture was adjusted to 6 withconcentrated HCl. EtOAc was added, and the mixture was washed with waterand brine, dried, and concentrated to dryness to afford(1S,2S)-2-(4-({5-[(5-chloropyridin-2-yl)thio]-2-cyclopropyl-1,3-oxazol-4-yl}phenyl)cyclopropanecarboxylicacid which was used in the next step with out further purification.LC/MS: m/z 413.1 (M+H)+.

Step E

The product from the previous step (30 mg, 0.073 mmol), HOBT (28 mg,0.182 mmol), and EDC (35 mg, 0.182 mmol) were dissolved in 1 ml, of DMF,to which were added Hunig's base (0.075 mL, 0.436 mmol) and dimethylamine (2 M THF solution, 0.363 mL, 0.727 mmol). The reaction was heatedat 75° C. for 45 min. Upon cooling to rt, the reaction was diluted withEtOAc and the reaction mixture was washed with water and brine, dried,and concentrated to dryness. The title compound was crystallized bydissolving in hot methanol then slowly cooling to −20° C. LC/MS: m/z440.1 (M+H)+. ¹H NMR (500 MHz, CD₃OD): δ 8.39 (s, 1H), 7.84 (d, 2H),7.71 (d, 1H), 7.20 (d, 2H), 7.06 (d, 1H), 3.16 (s, 3H), 2.97 (s, 3H),4.22 (m, 1H), 2.4-2.2 (br, 2H), 1.6-1.1 (br, 2H).

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention.

1.-20. (canceled)
 21. A method for treating a FAAH-mediated disease in anon-human animal comprising administering to the animal an effectiveamount of a compound of Formula I

or a pharmaceutically acceptable salt thereof wherein: X is S or SO; nis 0, 1 or 2; R¹ is selected from the group consisting of: (1) aryl, and(2) HET¹, wherein R¹ is optionally mono or di-substituted withsubstituents R⁴ and R⁵; and wherein R⁴ and R⁵ are independently selectedfrom the group consisting of: (a) halo, (b) —CN, (c) mono, di ortri-halo C₁₋₄ alkyl, (d) mono, di or tri-halo OC₁₋₄ alkyl, (d) —OC₁₋₄alkyl, optionally substituted with hydroxyl, halo or amino, (e)—C₁₋₄alkyl optionally substituted with one or two substituents selectedfrom hydroxyl, CN, —CHF₂ and —CF₃, (f) —C₁₋₂alkyl-C₃₋₆cycloalkyloptionally substituted with hydroxy, halo or CN, (g) —S(O)_(n)C₁₋₄alkyl,(h) —S(O)_(n)NR⁶R⁷, (i) —C(O)—NH—NR⁸R⁹, (j) —C(O)—OH, (k)—C(O)—OC₁₋₄alkyl, optionally substituted with halo or hydroxy, (l)—C(O)—NR¹⁰R¹¹, (m) —C(O)—C₁₋₄alkyl optionally mono, di or trisubstituted with halo, (o) —C(NR¹²)—NR¹³R¹⁴, (p) HET⁴, (q) aryl, (r)—C(O)—NH—NH—C(O)H, (s) —CH₂—C(O)—O—C₁₋₄alkyl, whereas the CH₂ may beoptionally substituted with C₁₋₄alkyl or OH (t) —CH₂—C(O)NR¹⁵R¹⁶,whereas the CH₂ may be optionally substituted with C₁₋₄alkyl or OH, and(u) —NR¹⁷R¹⁸, wherein choices (p) and (q) are each optionally mono ordi-substituted with substituents selected from (1) halo, (2) —CN, (3)—OH, (4) —C₁₋₄alkyl optionally substituted with hydroxy, halo or cyano,(5) —CF₃, (6) —OC₁₋₄alkyl optionally substituted with hydroxyl or halo,(7) —C(O)OH, and (8) —C(O)O—C₁₋₃alkyl; (9) —C(O)—NR¹⁹R²⁰, (10) —NH₂,(11) Oxo, (12) ═S, with the proviso that the substituent on choice (q)is other than oxo or ═S, wherein R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³,R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹ and R²⁰, are each independently selectedfrom H and C₁₋₄alkyl, or R⁶ and R⁷ or R⁸ and R⁹ or R¹⁰ and R¹¹ or R¹³and R¹⁴ or R¹⁵ and R¹⁶ or R¹⁷ and R¹⁸ or R¹⁹ and R²⁰ are joined togetherto form a ring with the atoms to which they are attached there is formeda 5-membered heterocyclic ring of 4 to 7 atoms, said ring containing 1,2, 3 or 4 heteroatoms selected from N, O and S, said ring beingoptionally mono or di-substituted with substituents independentlyselected from halo, hydroxyl, oxo, C₁₋₄alkyl, hydroxyC₁₋₄alkyl,haloC₁₋₄alkyl, —C(O)—C₁₋₄alkyl and —S(O)nC₁₋₄alkyl; R² is selected fromthe group consisting of: (1) aryl, (2) HET³, (3) —CH₂-aryl, (4)—CH₂-HET³, and (5) —C₃₋₆cycloalkyl, wherein R² is optionally mono ordi-substituted with substituents independently selected from the groupconsisting of (a) halo, (b) —CN, (c) —OH, (d) —C₁₋₄alkyl optionallysubstituted with hydroxy, halo or cyano, (e) —CF₃, (f) —OC₁₋₄alkyloptionally substituted with hydroxyl or halo, (g) —C(O)O—C₁₋₃alkyl and(h) —S-aryl, optionally substituted with halo, C₁₋₄alkyl or —OC₁₋₄alkyl;R³ is selected from the group consisting of: (1) HET⁵, and (2)C₃₋₆cycloalkyl, wherein R³ is optionally mono or di-substituted withsubstituents independently selected from the group consisting of (a)hydroxy, (b) halo, (c) —C₃₋₆cycloalkyl, (d) —OC₃₋₅cycloalkyl, (e) —OC₁₋₄alkyl, (f) —C(O)CH₃ (g) mono, di or tri-halo C₁₋₄ alkyl, (h) mono, di ortri-halo —OC₁₋₄ alkyl, and (i) —S(O)_(n)—C₁₋₄ alkyl; wherein HET¹, HET²,HET³, HET⁴ and HET⁵ are each independently a 5 to 10-membered aromatic,partially aromatic or non-aromatic mono- or bicyclic ring, or N-oxidethereof, said containing 1 to 4 heteroatoms selected from O, S and N,and optionally substituted with 1 to 2 oxo groups.
 22. The method ofclaim 21 wherein: R¹ is selected from the group consisting of: (1)phenyl, (2) pyridyl, (3) pyridazinyl, (4) pyrimidyl, (5) pyrazinyl, (6)thiazolyl, (7) thienyl, (8) pyrrolyl, (9) oxazolyl, and (10) oxadiazole;wherein R¹ is optionally mono or di-substituted with substituents R⁴ andR⁵, wherein R⁴ and R⁵ are independently selected from the groupconsisting of: (a) halo, (b) —CN, (c) mono, di or tri-halo C₁₋₄ alkyl,(d) —O—C₁₋₄alkyl, optionally substituted with hydroxyl, halo or amino(e) —C₁₋₄alkyl optionally substituted with hydroxyl or CN, (f)—C₁₋₂alkyl-C₃₋₆cycloalkyl optionally substituted with hydroxy, (h)—S(O)_(n)C₁₋₄alkyl wherein n is 0, 1 or 2, (i) —S(O)_(n)NR⁶R⁷, (j)—C(O)—NR¹⁰R¹¹, (k) HET⁴, (l) aryl, and wherein choices (k) and (l) areeach optionally mono or di-substituted with substituents selected from(1) halo, (2) —CN, (3) —OH, (4) —C₁₋₄alkyl optionally substituted withhydroxy, halo or cyano, (5) —CF₃, (6) —OC₁₋₄alkyl optionally substitutedwith hydroxyl or halo, (7) —C(O)OH, (8) —C(O)O—C₁₋₃alkyl, and (9)—C(O)—NR¹⁹R²⁰, wherein R⁶, R⁷, R¹⁰, R¹¹, R¹⁹ and R²⁰ are eachindependently selected from H and C₁₋₄alkyl.
 23. The method of claim 22wherein: R¹ is selected from the group consisting of: (1) phenyl, (2)pyridyl, (3) pyrimidyl, (4) pyrazinyl, (5) pyridazinyl, (6)1,2,4-oxadiazolyl, and (7) 1,3,4-oxadiazolyl, optionally mono ordi-substituted with substituents R⁴ and R⁵, which are independentlyselected from the group consisting of (a) —C₁₋₄alkyl optionallysubstituted with hydroxy, (b) —S(O)_(n)C₁₋₄alkyl, (c) —C(O)—NR¹⁰R¹¹, (d)HET⁴, and (e) halo, wherein HET⁴ is optionally mono or di-substitutedwith substituents selected from: (1) halo, (2) —CN, (3) —OH, (4)—C₁₋₄alkyl optionally substituted with hydroxy, halo or cyano, (5) —CF₃,(6) —OC₁₋₄alkyl optionally substituted with hydroxyl or halo, (7)—C(O)OH, and (8) —C(O)O—C₁₋₃alkyl, and (9) —C(O)—NR¹⁹R²⁰, wherein R¹⁰,R¹¹, R¹⁹ and R²⁰ are each independently selected from H and C₁₋₄alkyl.24. The method of claim 21 wherein: R² is selected from the groupconsisting of: (1) aryl, (2) HET³, (3) —CH₂aryl, and (4) —CH₂HET³,wherein R² is optionally mono or di-substituted with substituentsindependently selected from the group consisting of: (a) halo, (b) —CN,(c) —OH, (d) —Hydroxy C₁₋₄alkyl, (e) —C₁₋₄alkyl, (f) —C₁₋₄haloalkyl, and(g) —OC₁₋₄alkyl, optionally substituted with halo or hydroxyl.
 25. Themethod of claim 24 wherein: R² is selected from the group consisting of:(1) aryl, and (2) HET³, wherein R² is optionally mono or di-substitutedwith substituents independently selected from the group consisting of(a) halo, (b) —CN, (c) —OH, (d)-hydroxy C₁₋₄alkyl, (e) —CH₃, (f) —CF₃,and (g) —OCH₃.
 26. The method of claim 25 wherein: R² is selected fromthe group consisting of: (1) phenyl, (2) pyridyl, (3) pyridazinyl, (4)pyrimidyl, (5) pyrazinyl, (6) thiazolyl, (7) oxazolyl, (8) pyrazolyl,(9) 1,2,4-oxadiazolyl, and (10) 1,3,4-oxadiazolyl, wherein R² isoptionally mono or di-substituted with halo, OC₁₋₄alkyl optionallysubstituted with halogen, —C₁₋₄haloalkyl, hydroxyl and CN.
 27. Themethod of claim 21, wherein R³ is HET⁵, and wherein HET⁵ is optionallymono or di-substituted with substituents independently selected from thegroup consisting of: (a) halo, (b) —C₃₋₆cycloalkyl, (c) —OC₁₋₄ alkyl,(d) mono, di or tri-halo C₁₋₄ alkyl, and (e) mono, di or tri-halo —OC₁₋₄alkyl.
 28. The method of claim 27, wherein R³ is selected from the groupconsisting of: (1) pyrimidinyl, and (2) pyridyl, wherein R³ isoptionally mono or di-substituted with halo, haloC₁₋₄alkyl, or—OC₁₋₄alkyl optionally substituted with halo.
 29. The method of claim 21wherein X is S.
 30. The method of claim 21, comprising administering acompound of Formula Ia

wherein R¹ is selected from the group consisting of: (1) phenyl, (2)pyridyl, (3) pyridazinyl, (4) pyrimidyl, (5) pyrazinyl, (6) thiazolyl,(7) thienyl, (8) pyrrolyl, (9) oxazolyl, and (10) oxadiazole; wherein R¹is optionally mono or di-substituted with substituents R⁴ and R⁵, whichare independently selected from the group consisting of (a) halo, (b)—CN, (c) mono, di or tri-halo C₁₋₄ alkyl, (d) —O—C₁₋₄alkyl, optionallysubstituted with hydroxyl, halo or amino (e) —C₁₋₄alkyl optionallysubstituted with hydroxyl or CN, (f) —C₁₋₂alkyl-C₃₋₆cycloalkyloptionally substituted with hydroxy, (h) —S(O)_(n)C₁₋₄alkyl wherein n is0, 1 or 2, (i) —S(O)_(n)NR⁶R⁷, (j) —C(O)—NR¹⁰R¹¹, (k) HET⁴, and (l)aryl, wherein choices (k) and (l) are each optionally mono ordi-substituted with substituents selected from (1) halo, (2) —CN, (3)—OH, (4) —C₁₋₄alkyl optionally substituted with hydroxy, halo or cyano,(5) —CF₃, (6) —OC₁₋₄alkyl optionally substituted with hydroxyl or halo,(7) —C(O)OH, (8) —C(O)O—C₁₋₃alkyl, and (9) —C(O)—NR¹⁹R²⁰, wherein R⁶,R⁷, R¹⁰, R¹¹, R¹⁹ and R²⁰, are each independently selected from H andC₁₋₄alkyl; R² is selected from the group consisting of: (1) aryl, (2)HET³, and (3) —C₃₋₆cycloalkyl, wherein choice R² is optionally mono ordi-substituted with substituents independently selected from the groupconsisting of (a) halo, (b) —CN, (c) —OH, (d) -hydroxy C₁₋₄alkyl, (e)—C₁₋₄alkyl, (f) —C₁₋₄haloalkyl, and (g) —OC₁₋₄alkyl, optionallysubstituted with halo or hydroxyl; and R³ is HET⁵, wherein HET⁵ isoptionally mono or di-substituted with substituents independentlyselected from the group consisting of (a) halo, (b) —C₃₋₆cycloalkyl, (c)—OC₁₋₄ alkyl, (d) mono, di or tri-halo C₁₋₄ alkyl, and (e) mono, di ortri-halo —OC₁₋₄ alkyl.
 31. The method of claim 30 wherein R¹ is selectedfrom the group consisting of: (1) phenyl, (2) pyridyl, (3) pyrimidyl,(4) pyrazinyl, (5) pyridazinyl, (6) 1,2,4-oxadiazolyl, and (7)1,3,4-oxadiazolyl, optionally mono or di-substituted with substituentsR⁴ and R⁵, which are independently selected from the group consisting of(a) —C₁₋₄alkyl optionally substituted with hydroxy, (b)—S(O)_(n)C₁₋₄alkyl, (c) —C(O)—NR¹⁰R¹¹, (d) HET⁴, and (e) halo, whereinHET⁴ is optionally mono or di-substituted with substituents selectedfrom: (1) halo, (2) —CN, (3) —OH, (4) —C₁₋₄alkyl optionally substitutedwith hydroxy, halo or cyano, (5) —CF₃, (6) —OC₁₋₄alkyl optionallysubstituted with hydroxyl or halo, (7) —C(O)OH, and (8)—C(O)O—C₁₋₃alkyl, and (9) —C(O)—NR¹⁹R²⁰, wherein R¹⁰, R¹¹, R¹⁹ and R²⁰are each independently selected from H and C₁₋₄alkyl R² is selected fromthe group consisting of: (1) phenyl, (2) pyridyl, (3) pyridazinyl, (4)pyrimidyl, (5) pyrazinyl, (6) thiazolyl, (7) oxazolyl, (8) pyrazolyl,(9) 1,2,4-oxadiazolyl, and (10) 1,3,4-oxadiazolyl, wherein R² isoptionally mono or di-substituted with halo, OC₁₋₄alkyl optionallysubstituted with halogen, —C₁₋₄haloalkyl, hydroxyl and CN; and R³ isselected from the group consisting of: (1) pyrimidyl, and (2) pyridyl,wherein R³ is optionally mono or di-substituted with halo,haloC₁₋₄alkyl, or —OC₁₋₄alkyl optionally substituted with halo.
 32. Themethod of claim 21, comprising administering a compound of Formula Ia

wherein: R¹ is selected from the group consisting of: (1) phenyl, (2)pyridyl, (3) pyridazinyl, (4) pyrimidyl, (5) pyrazinyl, wherein R¹ isoptionally mono or di-substituted with substituents R⁴ and R⁵, which areindependently selected from the group consisting of: (a) halo, (b) —CN,(c) mono, di or tri-halo C₁₋₄ alkyl, (d) —O—C₁₋₄alkyl, optionallysubstituted with hydroxyl, halo or amino (e) —C(CH₃)₂—OH; R² is selectedfrom the group consisting of: (1) phenyl, (2) pyridyl, (3) pyridazinyl,(4) pyrimidyl, (5) pyrazinyl, (6) pyrazolyl, wherein R² is optionallymono or di-substituted with halo, OC₁₋₄alkyl optially substituted withhalogen, —C₁₋₄haloalkyl, hydroxyl and CN; and R³ is selected from thegroup consisting of: (1) pyrimidyl, and (2) pyridyl, wherein R³ isoptionally mono or di-substituted with halo, haloC₁₋₄alkyl, or—OC₁₋₄-alkyl optionally substituted with halo.
 33. The method of claim32 wherein: R¹ is selected from the group consisting of: (1) phenyl, (2)pyridyl, (3) pyrazinyl, wherein R¹ is optionally mono or di-substitutedwith substituents R⁴ and R⁵, which are independently selected from thegroup consisting of: (a) halo, (b) —CN, (c) mono, di or tri-halo C₁₋₄alkyl, (d) —O—C₁₋₄alkyl, optionally substituted with hydroxyl, halo oramino (e) —C(CH₃)₂—OH; R² is selected from the group consisting of: (1)phenyl, (2) pyridyl, wherein R² is optionally mono or di-substitutedwith halo, OC₁₋₄alkyl optially substituted with halogen, —C₁₋₄haloalkyl,hydroxyl and CN; and R³ is selected from the group consisting of: (1)pyrimidyl, and (2) pyridyl, wherein R³ is optionally mono ordi-substituted with halo, haloC₁₋₄alkyl, or —OC₁₋₄alkyl optionallysubstituted with halo.
 34. The method according to claim 21 wherein thecompound is selected from the group consisting of: (1)Methyl-5-[5-[(5-chloropyridin-2-yl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyrazine-2-carboxylate,(2) Methyl5-[5-[(5-chloropyridin-2-yl)thio]-2-(3-fluorophenyl)-1,3-oxazol-4-yl]pyrazine-2-carboxylate,(3)2-{5-[5-[(5-Chloropyridin-2-yl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyrazin-2-yl}propan-2-ol,(4)2-{5-[5-[(4-Chlorophenyl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyrazin-2-yl}propan-2-ol,(5)2-(5-{2-(4-Fluorophenyl)-5-[(4-methoxyphenyl)thio]-1,3-oxazol-4-yl}pyrazin-2-yl)propan-2-ol,(6)2-{5-[5-[(4-Chlorophenyl)thio]-2-(3-fluorophenyl)-1,3-oxazol-4-yl]pyrazin-2-yl}propan-2-ol,(7)2-(5-{2-(3-Fluorophenyl)-5-[(4-methoxyphenyl)thio]-1,3-oxazol-4-yl}pyrazin-2-yl)propan-2-ol,(8)2-{5-[5-[(5-Chloropyridin-2-yl)thio]-2-(3-fluorophenyl)-1,3-oxazol-4-yl]pyrazin-2-yl}propan-2-ol,(9)2-[5-[(4-Chlorophenyl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]-5-methylpyrazine,(10)2-{2-(3-Fluorophenyl)-5-[(4-methoxyphenyl)thio]-1,3-oxazol-4-yl}-5-methylpyrazine,(11)2-[5-[(4-Chlorophenyl)thio]-2-(3-fluorophenyl)-1,3-oxazol-4-yl]-5-methylpyrazine,(12)2-{5-[5-[(5-Chloropyridin-2-yl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyrazin-2-yl}propan-2-ol,(13)2-{5-[5-[(4-Chlorophenyl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyridin-2-yl}propan-2-ol,(14)2-(5-{2-(4-Fluorophenyl)-5-[(4-methoxyphenyl)thio]-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol,(15)2-{5-[5-[(2,4-Difluorophenyl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyridin-2-yl}propan-2-ol,(16)2-{5-[5-[(4-Chloro-2-fluorophenyl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyridin-2-yl}propan-2-ol,(17)2-{5-[5-[(3,4-Difluorophenyl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyridin-2-yl}propan-2-ol,(18)2-{5-[5-[(3-Fluoro-4-methoxyphenyl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyridin-2-yl}propan-2-ol,(19)2-(5-{2-(4-Fluorophenyl)-5-[(5-fluoropyridin-2-yl)thio]-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol,(20)2-{5-[5-[(5-Chloropyrimidin-2-yl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyridin-2-yl}propan-2-ol,(21)2-(5-{2-(4-Fluorophenyl)-5-[(6-methoxypyridin-3-yl)thio]-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol,(22)2-(5-{2-(4-Fluorophenyl)-5-[(5-fluoropyrimidin-2-yl)thio]-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol,(23)2-(5-{2-(4-Fluorophenyl)-5-[(5-methoxypyrimidin-2-yl)thio]-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol,(24)2-(5-{2-(4-Fluorophenyl)-5-[(2-methoxypyrimidin-5-yl)thio]-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol,(25)2-(5-{2-(4-Fluorophenyl)-5-[(5-methylpyridin-2-yl)thio]-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol,(26)2-{5-[5-[(5-Cyclopropylpyridin-2-yl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyridin-2-yl}propan-2-ol,(27)2-(5-{2-(4-Fluorophenyl)-5-[(2,4,5-trifluorophenyl)thio]-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol,(28)2-{5-[5-[(4-Chloro-3-fluorophenyl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyridin-2-yl}propan-2-ol,(29)2-{5-[5-[(4-Chlorophenyl)thio]-2-(3-fluorophenyl)-1,3-oxazol-4-yl]pyridin-2-yl}propan-2-ol,(30)2-(5-{2-(3-Fluorophenyl)-5-[(4-methoxyphenyl)thio]-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol,(31)2-{5-[5-[(5-Chloropyridin-2-yl)thio]-2-(3-fluorophenyl)-1,3-oxazol-4-yl]pyridin-2-yl}propan-2-ol,(32)2-{5-[5-[(5-Chloropyridin-2-yl)thio]-2-(3,5-difluorophenyl)-1,3-oxazol-4-yl]pyridin-2-yl}propan-2-ol,(33)2-(5-{2-(3,4-Difluorophenyl)-5-[(4-methoxyphenyl)thio]-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol,(34)2-{5-[5-[(4-Chlorophenyl)thio]-2-(3,4-difluorophenyl)-1,3-oxazol-4-yl]pyridin-2-yl}propan-2-ol,(35)2-{5-[5-[(5-Chloropyridin-2-yl)thio]-2-(3,4-difluorophenyl)-1,3-oxazol-4-yl]pyridin-2-yl}propan-2-ol,(36)2-{5-[5-[(5-Chloropyrimidin-2-yl)thio]-2-(3,4-difluorophenyl)-1,3-oxazol-4-yl]pyridin-2-yl}propan-2-ol,(37)2-{5-[5-[(5-Chloropyridin-2-yl)thio]-2-(4-fluoro-2-methylphenyl)-1,3-oxazol-4-yl]pyridin-2-yl}propan-2-ol,(38)2-(5-{2-(4-Chlorophenyl)-5-[(5-chloropyridin-2-yl)thio]-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol,(39)2-(5-{2-(4-Chlorophenyl)-5-[(5-fluoropyridin-2-yl)thio]-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol,(40)2-(5-{2-(4-Chlorophenyl)-5-[(5-chloropyrimidin-2-yl)thio]-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol,(41)2-(5-{2-(4-chloro-3-fluorophenyl)-5-[(4-chlorophenyl)thio]-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol,(42)2-(5-{2-(4-chloro-3-fluorophenyl)-5-[(5-chloropyridin-2-yl)thio]-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol,(43)2-(5-{2-(3-chloro-4-fluorophenyl)-5-[(4-chlorophenyl)thio]-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol,(44)2-(5-{2-(3-chloro-4-fluorophenyl)-5-[(5-chloropyridin-2-yl)thio]-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol,(45)2-{6-[5-[(5-Chloropyridin-2-yl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyridin-3-yl}propan-2-ol,(46)2-{6-[5-[(4-chlorophenyl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyridin-3-yl}propan-2-ol,(47)4-[5-[(4-Chlorophenyl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]benzonitrile,(48)3-{4-[5-[(4-Chlorophenyl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]phenyl}-1,2,4-oxadiazole,(49)4-{5-[(5-Chloropyridin-2-yl)thio]-4-[6-(1-hydroxy-1-methylethyl)pyridin-3-yl]-1,3-oxazol-2-yl}benzonitrile,(50)2-(5-{5-[(4-chlorophenyl)thio]-2-pyridin-2-yl-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol,(51)2-(5-{5-[(5-chloropyridin-2-yl)thio]-2-pyridin-2-yl-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol,(52)3-(4-({5-[(4-Chlorophenyl)thio]-2-phenyl-1,3oxazol-4-yl}phenyl)-1,2,4oxadiazole,(53)2-(4-{5-[(4-Chlorophenyl)thio]-2-phenyl-1,3oxazol-4-yl}phenyl)-1,3,4oxadiazole,(54)5-[(4-chlorophenyl)thio]-4-[4-(methylsulfonyl)phenyl]-2-phenyl-1,3-oxazole,and (55)2-{5-[(4-chlorophenyl)thio]-4-[4-(methylsulfonyl)phenyl]-1,3-oxazol-2-yl}pyridine,and (56)2-{5-[5-[(5-Chloropyridin-2-yl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyridin-2-yl}propan-2-ol;or a pharmaceutically acceptable salt thereof.
 35. The method accordingto claim 21, wherein the compound is selected from the group consistingof (1)5-Chloro-2-({2-(4-fluorophenyl)-4-[6-(1,2,4-oxadiazol-3-yl)pyridin-3-yl]-1,3-oxazol-5-yl}sulfanyl)pyridine,(2)5-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}pyrimidine-2-carbonitrile,(3)1-(5-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}pyrimidin-2-yl)ethanone,(4)2-(5-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}pyrimidin-2-yl)propan-2-ol,(5)5-Chloro-2-({2-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-1,3-oxazol-5-yl}sulfanyl)pyridine,(6)Methyl-4-{5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}benzoate,(7)2-(4-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}phenyl)propan-2-ol,(8)4-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}-1-(methylsulfonyl)piperidiniumtrifluoroacetate, (9) Methyl2-(5-{5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}pyridin-2-yl)-2-methylpropanoate,(10)3-(5-{5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}pyridin-2-yl)-2,3-dimethylbutan-2-ol(11)2-(5-{5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}pyridin-2-yl)-2-methylpropan-1-al,(12) Methyl5-{5-[(5-chloropyridin-2-yl)sulfanyl]-2-cyclopropyl-1,3-oxazol-4-yl)}pyridine-2-carboxylate,(13)1-(5-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-cyclopropyl-1,3-oxazol-4-yl}pyridin-2-yl)ethanone,(14)2-(5-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-cyclopropyl-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol,(15)2-(6-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}pyridazin-3-yl)propan-2-ol,(16) Ethyl5-{5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl)}isoxazole-3-carboxylate,(17)2-(5-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}isoxazol-3-yl)propan-2-ol,(18) Methyl2-{5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}-1,3-thiazole-4-carboxylate,(18)2-(2-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}-1,3-thiazol-4-yl)propan-2-ol,(19)5-Chloro-2-({2-cyclopropyl-4-[6-(methylsulfonyl)pyridin-3-yl]-1,3-oxazol-5-yl}sulfanyl)pyridine,(20)5-Chloro-2-({2-(4-fluorophenyl)-4-[6-(methylsulfonyl)pyridin-3-yl]-1,3-oxazol-5-yl}sulfanyl)pyridine,(21)5-Chloro-2-({2-(4-fluorophenyl)-4-[6-(methylsulfonyl)pyridin-3-yl]-1,3-oxazol-5-yl}sulfanyl)pyrimidine,(22)(R)-5-Chloro-2-({2-(4-fluorophenyl)-4-[6-(methylsulfinyl)pyridin-3-yl]-1,3-oxazol-5-yl}sulfanyl)pyridine,(23)(S)-5-Chloro-2-({2-(4-fluorophenyl)-4-[6-(methylsulfinyl)pyridine-3-yl]-1,3-oxazol-5-yl}sulfanyl)pyridine,(24)(R)-5-Fluoro-2-({2-(4-fluorophenyl)-4-[6-(methylsulfinyl)pyridin-3-yl]-1,3-oxazol-5-yl}sulfanyl)pyridine,(25)(S)-5-Fluoro-2-({2-(4-fluorophenyl)-4-[6-(methylsulfinyl)pyridin-3-yl]-1,3-oxazol-5-yl}sulfanyl)pyridine,(26) Methyl5-(5-[(4-chlorophenyl)sulfanyl]-2-(1-ethyl-1H-pyrazol-4-yl)-1,3-oxazol-4-yl)pyridine-2-carboxylate,(27)2-(5-{5-[(4-chlorophenyl)sulfanyl]-2-(1-ethyl-11H-pyrazol-4-yl)-1,3-oxazol-4-yl)pyridin-2-yl}propan-2-ol,(28) Methyl5-{5-[(5-chloropyridin-2-yl)sulfanyl]-2-(1-ethyl-1H-pyrazol-4-yl)-1,3-oxazol-4-yl)pyridine-2-carboxylate,(29)2-(5-{5-[(5-chloropyridin-2-yl)sulfanyl]-2-(1-ethyl-1H-pyrazol-4-yl)-1,3-oxazol-4-yl}pyridin-2-yl}propan-2-ol,(30)5-Chloro-2-({2-(4-fluorophenyl)-4-[6-(methylsulfanyl)pyridin-3-yl]-1,3-oxazol-5-yl}sulfanyl)pyridine,(31) Methyl5-{5-[(5-chloropyridin-2-yl)sulfanyl]-2-cyclobutyl-1,3-oxazol-4-yl}pyridine-2-carboxylate,(32)2-(5-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-cyclobutyl-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol,(33)1-(5-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-cyclobutyl-1,3-oxazol-4-yl}pyridin-2-yl)ethanone,(34)(R)-1-(5-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-cyclobutyl-1,3-oxazol-4-yl}pyridin-2-yl)ethanol,(35)(S)-1-(5-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-cyclobutyl-1,3-oxazol-4-yl}pyridin-2-yl)ethanol,(36) Methyl5-{2-(5-chloropyridin-3-yl)-5-[(5-chloropyridin-2-yl)sulfanyl]-1,3-oxazol-4-yl}pyridine-2-carboxylate,(37)2-(5-{2-(5-Chloropyridin-3-yl)-5-[(5-chloropyridin-2-yl)sulfanyl]-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol,(38)1-(5-{2-(5-Chloropyridin-3-yl)-5-[(5-chloropyridin-2-yl)sulfanyl]-1,3-oxazol-4-yl}pyridin-2-yl)ethanone,(39)(5-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}pyridin-2-yl)acetonitrile,(40)1-(5-{(5-[(5-Chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}pyridin-2-yl)-3-hydroxycyclobutanecarbonitrile,(41)2-(5-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-(4-fluorobenzyl)-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol,(42) Methyl2-{5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}pyrimidine-5-carboxylate,(43)6-{5-[(4-Chlorophenyl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}-3,4-dihydroisoquinolin-1(2H)-one,(44)7-{5-[(4-Chlorophenyl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}-3-(difluoromethyl)quinoline,(45)6-{5-[(4-Chlorophenyl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}-2-(difluoromethyl)quinoline,(46)6-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}-N,N-dimethylquinoline-2-carboxamide,(47)3-{5-[(5-Chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}-6-(methylsulfonyl)pyridazine,and (48)(1S,2S)-2-(4-{5-[(5-chloropyridin-2-yl)thio]-2-cyclopropyl-1,3-oxazol-4-yl}phenyl)-N,N-dimethylcyclopropanecarboxamide,and (49)2-{5-[5-[(5-Chloropyridin-2-yl)thio]-2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyridin-2-yl}propan-2-ol,or a pharmaceutically acceptable salt thereof.
 36. The method of claim21, wherein the compound is selected from a compound having the formula

R₂ R₃

or

R₁ R₃

or

R₁ R₃

or

R₁ R₂

or

R₃

or a pharmaceutically acceptable salt thereof.
 37. The method of claim21 wherein the compound is


38. The method of claim 21, wherein the disease is selected from thegroup consisting of: osteoarthritis, pain and sleep disorder.
 39. Themethod of claim 38, wherein the pain is skeletomuscular pain or acutepain.
 40. The method of claim 21, wherein the non-human animal is a dog.